18.918.9The Aldol CondensationThe Aldol Condensation

A basic solution contains comparable amounts A basic solution contains comparable amounts of the aldehyde and its enolate.of the aldehyde and its enolate.

Aldehydes undergo nucleophilic addition.Aldehydes undergo nucleophilic addition.

Enolate ions are nucleophiles.Enolate ions are nucleophiles.

What about nucleophilic addition of enolate to What about nucleophilic addition of enolate to aldehyde?aldehyde?

RCHRCH22CHCH

OO

++ ••••OHOH••••

••••––

RCHCHRCHCH

OO

++ ••••HOHHOH

••••––••••ppKKaa = 16-20 = 16-20 ppKKaa = 16 = 16

Some thoughts...Some thoughts...

••••RCHCHRCHCH

OO•••• ••••

––

RCHRCH22CHCH

OO••••

••••

••••RCHCHRCHCH

OO•••• ••••

––

RCHRCH22CHCH

OO••••

••••

––

RCHRCH22CHCH

OO••••

••••

•••• ••••

RCHCHRCHCH

OO

••••

RCHRCH22CHCH

OO••••

•••• ••••

RCHCHRCHCH

OO

•••• HH

••••RCHCHRCHCH

OO•••• ••••

––

RCHRCH22CHCH

OO••••

••••

––

RCHRCH22CHCH

OO••••

••••

•••• ••••

RCHCHRCHCH

OO

••••••••

RCHRCH22CHCH

OO

•••• ••••

RCHCHRCHCH

OO

•••• HH

2RCH2RCH22CHCH

OONaOHNaOH

RCHRCH22CHCH

OHOH

CHCHCHCH

OO

RR

product is called an "aldol" because it is product is called an "aldol" because it is both an aldehyde and an alcoholboth an aldehyde and an alcohol

Aldol AdditionAldol Addition

RCHRCH22CHCH

OHOH

CHCHCHCH

OO

RR

Aldol Addition of AcetaldehydeAldol Addition of Acetaldehyde

AcetaldolAcetaldol(50%)(50%)

NaOH, HNaOH, H22OO

5°C5°C2CH2CH33CHCH

OO

CHCH33CHCH

OHOH

CHCH22CHCH

OO

Aldol Addition of ButanalAldol Addition of Butanal

(75%)(75%)

KOH, HKOH, H22OO 6°C6°C

2CH2CH33CHCH22CHCH22CHCH

OO

CHCH33CHCH22CHCH22CHCH

OHOH

CHCHCHCH

OO

CHCH22CHCH33

2RCH2RCH22CHCH

OONaOHNaOH

RCHRCH22CHCH

OHOH

CHCHCHCH

OO

RR

Aldol CondensationAldol Condensation

2RCH2RCH22CHCH

OONaOHNaOH

RCHRCH22CHCH

OHOH

CCHHCHCH

OO

RR

Aldol CondensationAldol Condensation

2RCH2RCH22CHCH

OONaOHNaOH

RCHRCH22CHCH

OHOH

CCHHCHCH

OO

RR

Aldol CondensationAldol Condensation

heatheat

RCHRCH22CHCH CCHCCH

OO

RR

2RCH2RCH22CHCH

OONaOHNaOH

RCHRCH22CHCH

OHOH

CCHHCHCH

OO

RR

Aldol CondensationAldol Condensation

heatheat

RCHRCH22CHCH CCHCCH

OO

RR

NaOHNaOHheatheat

Aldol Condensation of ButanalAldol Condensation of Butanal

NaOH, HNaOH, H22OO 80-100°C80-100°C

2CH2CH33CHCH22CHCH22CHCH

OO

Aldol Condensation of ButanalAldol Condensation of Butanal

(86%)(86%)

NaOH, HNaOH, H22OO 80-100°C80-100°C

2CH2CH33CHCH22CHCH22CHCH

OO

CHCH33CHCH22CHCH22CHCH CCHCCH

OO

CHCH22CHCH33

dehydration of dehydration of -hydroxy aldehyde can be-hydroxy aldehyde can becatalyzed by either acids or basescatalyzed by either acids or bases

Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product

CC OO

CC

CCOHOH

HHCC OO

CC

CC

in base, the enolate is formed in base, the enolate is formed

Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product

OHOH

HHCC OO

CC

CC

NaOHNaOH

OHOH

CC OO

CC

CC

••••––

the enolate loses hydroxide to form the the enolate loses hydroxide to form the ,,-unsaturated aldehyde-unsaturated aldehyde

Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product

OHOH

HHCC OO

CC

CC

NaOHNaOH

OHOH

CC OO

CC

CC

••••––

Aldol reactions of ketonesAldol reactions of ketones

the equilibrium constant for aldol addition the equilibrium constant for aldol addition reactions of ketones is usually unfavorablereactions of ketones is usually unfavorable

2%2%

98%98%2CH2CH33CCHCCH33

OO OO

CHCH33CCHCCH22CCHCCH33

OHOH

CHCH33

Intramolecular Aldol CondensationIntramolecular Aldol Condensation

NaNa22COCO33, H, H22O O

heatheat

OO

OO

OO

OHOH

OO

(96%)(96%)

via:via:

Intramolecular Aldol CondensationIntramolecular Aldol Condensation

NaNa22COCO33, H, H22O O

heatheat

OO

OO

OO

(96%)(96%)

even ketones give good yields of aldol even ketones give good yields of aldol condensation products when the reaction is condensation products when the reaction is intramolecular intramolecular

18.1018.10Mixed Aldol CondensationsMixed Aldol Condensations

What is the product?What is the product?

There are 4 possibilities because the There are 4 possibilities because the reaction mixture contains the two reaction mixture contains the two aldehydes plus the enolate of each aldehydes plus the enolate of each aldehyde.aldehyde.

NaOHNaOHCHCH33CHCH

OO

CHCH33CHCH22CHCH

OO

++

What is the product?What is the product?

CHCH33CHCH

OO

CHCH33CHCH22CHCH

OO

++

CHCH22CHCH

OO

CHCH33CHCHCHCH

OO

••••––

••••

––

CHCH33CHCH

OHOH

CHCH22CHCH

OO

What is the product?What is the product?

CHCH33CHCH

OO

CHCH33CHCH22CHCH

OO

++

CHCH22CHCH

OO

CHCH33CHCHCHCH

OO

••••––

••••

––

CHCH33CHCH22CHCH

OHOH

CHCHCHCH

OO

CHCH33

What is the product?What is the product?

CHCH33CHCH

OO

CHCH33CHCH22CHCH

OO

++

CHCH22CHCH

OO

CHCH33CHCHCHCH

OO

••••––

••••

––

CHCH33CHCH

OHOH

CHCHCHCH

OO

CHCH33

What is the product?What is the product?

CHCH33CHCH

OO

CHCH33CHCH22CHCH

OO

++

CHCH22CHCH

OO

CHCH33CHCHCHCH

OO

••••––

••••

––

CHCH33CHCH22CHCH

OHOH

CHCH22CHCH

OO

In order to effectively carry outIn order to effectively carry outa mixed aldol condensation:a mixed aldol condensation:

need to minimize reaction possibilitiesneed to minimize reaction possibilitiesusually by choosing one component that cannot usually by choosing one component that cannot form an enolateform an enolate

FormaldehydeFormaldehyde

formaldehyde cannot form an enolateformaldehyde cannot form an enolateformaldehyde is extremely reactive toward formaldehyde is extremely reactive toward nucleophilic additionnucleophilic addition

OO

HCHHCH

FormaldehydeFormaldehyde

OO

HCHHCH ++ (CH(CH33))22CHCHCHCH22CHCH

OO

(CH(CH33))22CHCHCHCHCHCH

OO

CHCH22OHOH

(52%)(52%)

KK22COCO33

water-water-etherether

Aromatic AldehydesAromatic Aldehydes

CHCH33OO CHCH

OO

aromatic aldehydes cannot form an enolatearomatic aldehydes cannot form an enolate

Aromatic AldehydesAromatic Aldehydes

CHCH33OO CHCH

OO

++ CHCH33CCHCCH33

OO

NaOH, HNaOH, H22OO 30°C30°C

CHCH33OO CHCH

CHCCHCHCCH33

OO

(83%)(83%)