18.618.6

Base-Catalyzed Enolization:Base-Catalyzed Enolization:

Enolate AnionsEnolate Anions

Acidity of Acidity of -Hydrogen-Hydrogen

+ + HH++RR22CC CR'CR'

OO•••• ••••

––

••••

OO••••

RR22CC CR'CR'

••••

HH

ppKKaa = 16-20 = 16-20

Acidity of Acidity of -Hydrogen-Hydrogen

+ + HH++

RR22CC CR'CR'

OO••••

•••• ••••––

••••

RR22CC CR'CR'

OO ••••

––

••••

OO••••

RR22CC CR'CR'

••••

HH

ppKKaa = 16-20 = 16-20

Acidity of Acidity of -Hydrogen-Hydrogen

OO••••

RR22CC CR'CR'

••••

HH

ppKKaa = 16-20 = 16-20

enolate ionenolate ion

+ + HH++

••••

RR22CC CR'CR'

OO•••• ••••––

RR22CC CR'CR'

OO•••• ••••

––

••••

Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)

OO••••

RR22CC CR'CR'

HH

OO

HH

•••••••••••• ––

••••

Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)

HHOO

HH

••••••••

OO••••

RR22CC CR'CR'

––••••••••

Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)

OO

HH

HH ••••OO••••

RR22CC CR'CR'

––••••••••••••

Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)

OO

HH

HH ••••

OO••••

RR22CC CR'CR'

––••••••••••••

Mechanism of EnolizationMechanism of Enolization(Base-catalyzed)(Base-catalyzed)

HHOO••••

RR22CC CR'CR'

•••• OO

HH

••••––••••

••••

Acidity of Acidity of -Hydrogen-Hydrogen

ppKKaa = 15.5 = 15.5 ppKKaa = 15.8 = 15.8

(CH(CH33))22CCHHCHCH

OO CCCCHH33

OO

-Diketones are much more acidic-Diketones are much more acidic

CHCH33CCCCHH22CCHCCH33

OO OO

ppKKaa = 9 = 9

HH33CCCC

CHCH33

OO

CCCC

OO

HH HH

HH33CCCC

CHCH33

OO

CCCC

OO

HH

HH++++••••––

-Diketones are much more acidic-Diketones are much more acidic

KKaa = 10 = 10–9–9

HH33CCCC

CHCH33

OO

CCCC

OO

HH

••••––

-Diketones are much more acidic-Diketones are much more acidic

enolate of enolate of -diketone is stabilized; negative -diketone is stabilized; negative charge is shared by both oxygenscharge is shared by both oxygens

-Diketones are much more acidic-Diketones are much more acidic

HH33CCCC

CHCH33

OO

CCCC

OO

HH

••••––

•••• ••••••••••••

HH33CCCC

CHCH33

OO

CCCC

OO

HH

–– •••• •••••••••••• ••••

-Diketones are much more acidic-Diketones are much more acidic

HH33CCCC

CHCH33

OO

CCCC

OO

HH

••••––

•••• ••••••••••••

HH33CC

––

HH

CCCHCH33

OO

CCCC

OO•••• ••••

•••••••• ••••

18.718.7

The Haloform ReactionThe Haloform Reaction

Under basic conditions, halogenation of a Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon methyl ketone often leads to carbon-carbon bond cleavage.bond cleavage.

Such cleavage is called the haloform reaction Such cleavage is called the haloform reaction because chloroform, bromoform, or iodoform because chloroform, bromoform, or iodoform is one of the products.is one of the products.

The Haloform ReactionThe Haloform Reaction

ExampleExample

(CH(CH33))33CCCCCCHH33

OO

BrBr22, NaOH, H, NaOH, H22OO

CCHBrHBr33++(CH(CH33))33CCONaCCONa

OO

(CH(CH33))33CCOHCCOH

OO

HH++

(71-74%)(71-74%)

The haloform reaction is sometimes used as a The haloform reaction is sometimes used as a method for preparing carboxylic acids, but method for preparing carboxylic acids, but works well only when a single enolate can works well only when a single enolate can form.form.

The Haloform ReactionThe Haloform Reaction

ArCArCCHCH33

OO

(CH(CH33))33CCCCCHCH33

OO

RRCHCH22CCCHCH33

OO

yesyes yesyes nono

RCCHRCCH33

OO

XX22, HO, HO––

RCCHRCCH22XX

OOXX22, HO, HO––

RCCHRCCHXX22

OO

XX22, HO, HO––

RCCRCCXX33

OO

MechanismMechanism

First stage is substitution of all available First stage is substitution of all available hydrogens by halogenhydrogens by halogen

MechanismMechanism

Formation of the trihalomethyl ketone is Formation of the trihalomethyl ketone is followed by its hydroxide-induced cleavagefollowed by its hydroxide-induced cleavage

HOHO •••• ––••••

••••

•••• ––

RCRC

OO ••••

HOHO ••••••••

••••

CCXX33RCRC

OO ••••••••

CCXX33

––•••• CCXX33

••••

RCRC

OO ••••

OHOH••••

••••

++

++––•••• HCHCXX33

••••

RCRC

OO ••••

OO••••

••••++

18.818.8

Some Chemical and StereochemicalSome Chemical and Stereochemical

Consequences of EnolizationConsequences of Enolization

Hydrogen-Deuterium ExchangeHydrogen-Deuterium Exchange OO

HH

HH HH

HH++ 44DD22OO OO

DD

DD DD

DD++ 44DDOHOH

KOKODD, heat, heat

MechanismMechanism

OODD••••––

••••

••••++

HOHODD

••••

••••++HH

OO

HH

HH

••••––•••• ••••

OO

HH

HH

HH

••••••••

HH

MechanismMechanism

HH

OO

HH

HH

••••––•••• ••••

MechanismMechanism

OODD••••––

••••

••••++

HH

OO

HH

HH

••••––•••• ••••

OO

HH

HH

DD

••••••••

HH

OODD••••

••••DD

Stereochemical Consequences of EnolizationStereochemical Consequences of Enolization CC CCCC66HH55

OOHH

CHCH33CHCH22

HH33CC

100% R100% R

HH33OO++

HH22O, HOO, HO––

50% R50% S

50% R50% S

50% R50% S

50% R50% S

Enol is achiralEnol is achiral CC CCCC66HH55

OOHH

CHCH33CHCH22

HH33CC

RR

CCCC66HH55

OHOH

CC

HH33CC

CHCH33CHCH22

Enol is achiralEnol is achiral CC CCCC66HH55

OOHH

CHCH33CHCH22

HH33CC

RR

CCCC66HH55

OHOH

CC

HH33CC

CHCH33CHCH22

CC CCCC66HH55

OOHH

CHCH33CHCH22

HH33CC

SS50%50%

50%50%

Results of Rate StudiesResults of Rate Studies CC CCCC66HH55

OOHH

CHCH33CHCH22

HH33CC

Equal rates for:Equal rates for:racemizationracemizationH-D exchangeH-D exchangebrominationbrominationiodinationiodination

Enol is intermediate Enol is intermediate and its formation is and its formation is rate-determiningrate-determining