18.9 The Aldol Condensation

A basic solution contains comparable amounts of the aldehyde and its enolate. Aldehydes undergo nucleophilic addition. Enolate ions are nucleophiles. What about nucleophilic addition of enolate to aldehyde? RCH 2 CH O+ OH – RCHCHO+HOH – pK a = pK a = 16 Some thoughts...

RCHCH O – RCH 2 CH O

RCHCH O – RCH 2 CH O – RCH 2 CH O RCHCH O RCH 2 CH O RCHCH O H

RCHCH O – RCH 2 CH O – RCH 2 CH O RCHCH O RCH 2 CH O RCHCH O H 2RCH 2 CH ONaOH RCH 2 CH OH CHCHOR

product is called an "aldol" because it is both an aldehyde and an alcohol Aldol Addition RCH 2 CH OH CHCHOR

Aldol Addition of Acetaldehyde Acetaldol (50%) NaOH, H 2 O 5°C 2CH 3 CH O CH 3 CH OH CH 2 CH O

Aldol Addition of Butanal (75%) KOH, H 2 O 6°C 2CH 3 CH 2 CH 2 CH O CH 3 CH 2 CH 2 CH OH CHCHO CH 2 CH 3

2RCH 2 CH ONaOH RCH 2 CH OH CHCHOR Aldol Condensation

2RCH 2 CH ONaOH RCH 2 CH OH CHCH OR Aldol Condensation

2RCH 2 CH ONaOH RCH 2 CH OH CHCH OR Aldol Condensation heat RCH 2 CH CCHOR

2RCH 2 CH ONaOH RCH 2 CH OH CHCH OR Aldol Condensation heat RCH 2 CH CCHOR NaOH heat

Aldol Condensation of Butanal NaOH, H 2 O °C 2CH 3 CH 2 CH 2 CH O

Aldol Condensation of Butanal (86%) NaOH, H 2 O °C 2CH 3 CH 2 CH 2 CH O CH 3 CH 2 CH 2 CH CCHO CH 2 CH 3

dehydration of  -hydroxy aldehyde can be catalyzed by either acids or bases Dehydration of Aldol Addition Product C O C C OH H C O C C

in base, the enolate is formed Dehydration of Aldol Addition Product OH H C O C C NaOH OH C O C C –

the enolate loses hydroxide to form the ,  -unsaturated aldehyde Dehydration of Aldol Addition Product OH H C O C C NaOH OH C O C C –

Aldol reactions of ketones the equilibrium constant for aldol addition reactions of ketones is usually unfavorable 2%98% 2CH 3 CCH 3 O O CH 3 CCH 2 CCH 3 OH CH 3

Intramolecular Aldol Condensation Na 2 CO 3, H 2 O heatOO OOH O(96%) via:

Intramolecular Aldol Condensation Na 2 CO 3, H 2 O heatOO O(96%) even ketones give good yields of aldol condensation products when the reaction is intramolecular

18.10 Mixed Aldol Condensations

What is the product? There are 4 possibilities because the reaction mixture contains the two aldehydes plus the enolate of each aldehyde. NaOH CH 3 CH O CH 3 CH 2 CH O+

What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH OH CH 2 CH O

What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH 2 CH OH CHCHO CH 3

What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH OH CHCHO CH 3

What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH 2 CH OH CH 2 CH O

In order to effectively carry out a mixed aldol condensation: need to minimize reaction possibilities usually by choosing one component that cannot form an enolate

Formaldehyde formaldehyde cannot form an enolate formaldehyde is extremely reactive toward nucleophilic addition OHCH

FormaldehydeOHCH + (CH 3 ) 2 CHCH 2 CH O (CH 3 ) 2 CHCHCH O CH 2 OH (52%) K 2 CO 3 water- ether

Aromatic Aldehydes CH 3 O CHO aromatic aldehydes cannot form an enolate

Aromatic Aldehydes CH 3 O CHO+ CH 3 CCH 3 O NaOH, H 2 O 30°C CH 3 O CH CHCCH 3 O(83%)