under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage....
TRANSCRIPT
Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage.
Such cleavage is called the haloform reaction because chloroform, bromoform, or iodoform is one of the products.
The Haloform ReactionThe Haloform Reaction
O
CR CH3
Halogen+
NaOH
solventthen H+
O
CR OH
H
CXX
X
Chloroform
H
CBrBr
Br
H
CClCl
Cl
H
CII
I
IodoformBromoform
ExampleExample
H
CBrBr
Br
Bromoform
O
CH3
CH3
CH3
CH3
O
O- K+CH3
CH3
CH3
Br2
NaOHH2O
O
OCH3
CH3
CH3
H+
H
The Haloform ReactionThe Haloform Reaction
O
CH3
O
OH
O
CH3
H3CO
OH
H3C
The haloform reaction is sometimes used as a method for preparing carboxylic acids, but works well only when a single enolate can form.
The Haloform ReactionThe Haloform Reaction
The haloform reaction is sometimes used as a method for preparing carboxylic acids, but works well only when a single enolate can form.
O
CH3
HO
OH
H
O
C
HO
CH3
H
H
Deprotonation can lead to two different enolates
InefficientReaction
MechanismMechanismFirst stage of a haloform reaction is substitution of all available hydrogens by halogen atoms.
R
O
CH
HH
R
O
CH
H
X2
R
O
CH
HX
Deprotonation
HO-
Halogenation
Hydrogen is more acidicthan in s.m.HO-
K1
K2K1 < K2
R
O
CH
X
R
O
CX
HX
X2
HalogenationR
O
CX
XX
MechanismMechanismFormation of the tri--halomethyl ketone is followed by its hydroxide-induced cleavage
R
O
CX
XX
R
O
CX
X
R
O
OH
NucleophilicAddition
HO-
Carbon-CarbonBond Cleavage
H O
HO X
UnstableIntermediate
X
XX
R
O
O
X
XX
Proton Transfer
H
Carboxylate Anion Haloform
Proton Transfer
H+
R
O
O
Carboxylic Acid
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
••••––•••• ••••
OODD••••––
••••
••••++
OO
HH
HH
DD
••••••••
HH
OODD••••
••••DD
Bridgehead Bridgehead
Carbonyl Carbonyl
Compounds?Compounds?
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:racemizationH-D exchangebrominationiodination
Enol is intermediate and its formation is rate-determining
18.918.9
The Aldol CondensationThe 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?
RCHRCH22CHCH
OO
++ ••••OHOH••••
••••––
RCHCHRCHCH
OO
++ ••••HOHHOH
••••––••••ppKKaa = 16-20 = 16-20 ppKKaa = 16 = 16
Some thoughts...Some thoughts...
O
HR
H
O
HR
Nucleophilic1,2-Addition
RH
OH
HO
R
Protonation
RH
OH
HOH
R
Aldol Product
( Hydroxy Carbonyl Compound)
This product is called an "aldol" because it is
both an aldehyde and an alcohol
Aldol AdditionAldol Addition
RH
OH
HOH
R
Aldol Product
( Hydroxy Carbonyl Compound)
Aldol Addition of AcetaldehydeAldol Addition of Acetaldehyde
O
HH
H
O
HH3C
Nucleophilic1,2-Addition H
OH
HH3CO
Protonation
'Aldol'
3-hydroxybutanal
(50%)
NaOHH2O
O
HH3C
H O
HH3C
OH
nucleophilic enolate
electrophilic aldehyde
Aldol Addition of n-ButanalAldol Addition of n-Butanal
O
H
OH O
H
KOHH2O
6 °C(75%)
2 x n-Butanal
Aldol Product(-Hydroxy ketone)
Aldol AdditionReaction
newly formedcarbon-carbon bond
Aldol CondensationAldol Condensation
O
HR
OH
R
R
O
H
KOHH2O
Aldol AdditionReaction
H
HH
R
R
O
H
Aldol CondensationReaction
Heat, -H2O
Dehydration
HeatKOH
Dehydration Product
Aldol Condensation of ButanalAldol Condensation of Butanal
O
H
O
H
KOHH2O
100 °C(86%)
2 x n-Butanal
-Unsaturated Ketone
Aldol CondensationReaction
newly formedcarbon-carbon double bond
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
O
CH3H3C
2 x Acetone
O
CH3H3C
OHH3C
Formation of Aldol Product from Acetone
is not thermodynamically
favorable: cf. hydration of acetone
[4-hydroxy-4-methylpentan-2-one]
2%
98%
Intramolecular Aldol CondensationIntramolecular Aldol Condensation
O
O
O
O
Deprotonation
Na2CO3, H2O
heat
O
O
IntramolecularAldol Addition
Protonation&
Dehydration
O
even ketones give good yields of aldol condensation products when the reaction is intramolecular
InformationInformation
Suggested Problems: 18.26-18.37Suggested Problems: 18.26-18.37
New Chp. 15 & 17 problem set now availableNew Chp. 15 & 17 problem set now available
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