18.7 ? Halogenation of Aldehydes and Ketones

1
18.7 ? Halogenation ofAldehydes and Ketones
2
General Reaction


X2
HX

• X2 is Cl2, Br2, or I2.
• Substitution is specific for replacement of
  ??hydrogen.
• Catalyzed by acids. One of the products is an
  acid (HX) the reaction is autocatalytic.
• Not a free-radical reaction.

3
Example
H2O
(61-66)
4
Example
CHCl3


HBr
Br2
(80)

• Notice that it is the proton on the ? carbon
  that is replaced, not the one on the carbonyl
  carbon.

5
18.8 Mechanism of ? Halogenation ofAldehydes
and Ketones
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Mechanism of ? Halogenation
Experimental Facts

• specific for replacement of H at the ? carbon
• equal rates for chlorination, bromination, and
  iodination
• first order in ketone zero order in halogen

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Mechanism of ? Halogenation
Two stages

• first stage is conversion of aldehyde or ketone
  to the corresponding enol is rate-determining
• second stage is reaction of enol with halogen
  is faster than the first stage

8
Mechanism of ? Halogenation
9
Mechanism of ? Halogenation
Two stages

• first stage is conversion of aldehyde or ketone
  to the corresponding enol is rate-determining
• second stage is reaction of enol with halogen
  is faster than the first stage

examine second stage now
10
Reaction of enol with Br2

• carbocation is stabilized by electron release
  from oxygen

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Loss of proton from oxygen completes the process

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18.9The Haloform Reaction
13
The Haloform Reaction

• 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.

14
Example
Br2, NaOH, H2O

CHBr3
H
(71-74)
15
The 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.

yes
yes
no
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Mechanism

• First stage is substitution of all available
  ??hydrogens by halogen

X2, HO
X2, HO
X2, HO
17
Mechanism

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

18
18.10Some Chemical and StereochemicalConsequence
s of Enolization
19
Hydrogen-Deuterium Exchange

4D2O
KOD, heat

4DOH
20
Mechanism

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Mechanism
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Stereochemical Consequences of Enolization
H3O
50 R50 S
50 R50 S
100 R
H2O, HO
23
Enol is achiral
R
24
Enol is achiral
H3C
H
CC6H5
S
50
CH3CH2
50
R
25
Results of Rate Studies

• Equal rates for racemization H-D
  exchange bromination iodination
• Enol is intermediate and its formation is
  rate-determining

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18.11Effects of Conjugation in ???-Unsaturated
Aldehydes and Ketones
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Relative Stability

• aldehydes and ketones that contain a
  carbon-carbon double bond are more stable when
  the double bond is conjugated with the carbonyl
  group than when it is not
• compounds of this type are referred to as ?,?
  unsaturated aldehydes and ketones

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Relative Stability
29
Acrolein
30
Acrolein
31
Acrolein
32
Acrolein
33
Resonance Description
34
Properties

• ???-Unsaturated aldehydes and ketones are more
  polar than simple aldehydes and ketones.
• ???-Unsaturated aldehydes and ketones contain
  two possible sites for nucleophiles to attack
• carbonyl carbon
• ?-carbon

35
Dipole Moments
?
?
?
?
?

Butanal
trans-2-Butenal

• greater separation of positive and negative
  charge

36
18.12Conjugate Addition to ???-Unsaturated
Carbonyl Compounds
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Nucleophilic Addition to ???-Unsaturated
Aldehydes and Ketones

• 1,2-addition (direct addition)
• nucleophile attacks carbon of CO
• 1,4-addition (conjugate addition)
• nucleophile attacks ?-carbon

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Kinetic versus Thermodynamic Control

• attack is faster at CO
• attack at ?-carbon gives the more stable product

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1,2-addition

• formed faster
• major product under conditions of kinetic
  control (i.e. when addition is not readily
  reversible)

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1,4-addition

• enol
• goes to keto form under reaction conditions

41

1,4-addition

• keto form is isolated product of 1,4-addition
• is more stable than 1,2-addition product

42

1,2-addition
1,4-addition
CO is stronger than CC
43
1,2-Addition

• observed with strongly basic nucleophiles
• Grignard reagents
• LiAlH4
• NaBH4
• Sodium acetylide
• strongly basic nucleophiles add irreversibly

44
Example
1. THF2. H3O
45
1,4-Addition

• observed with weakly basic nucleophiles
• cyanide ion (CN)
• thiolate ions (RS)
• ammonia and amines
• azide ion (N3)
• weakly basic nucleophiles add reversibly

46
Example
(93-96)
47
Example
O
C6H5CH2SH
HO, H2O
(58)
48
18.13Addition of Carbanions to???-Unsaturated
Carbonyl CompoundsThe Michael Reaction
49
Michael Addition

• Stabilized carbanions, such as those derived
  from ?-diketones undergo conjugateaddition to
  ?,?-unsaturated ketones.

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Example


KOH, methanol
(85)
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Michael Addition

• The Michael reaction is a useful method
  forforming carbon-carbon bonds.
• It is also useful in that the product of the
  reaction can undergo an intramolecularaldol
  condensation to form a six-membered ring. One
  such application is called the Robinsonannulation
  .

52
Example
NaOHheat
not isolateddehydrates under reaction conditions
53
18.14Conjugate Addition of Organocopper
Reagentsto ???-Unsaturated Carbonyl Compounds
54
Addition of Organocopper Reagents
to???-Unsaturated Aldehydes and Ketones

• The main use of organocopper reagents is toform
  carbon-carbon bonds by conjugate addition to
  ?,?-unsaturated ketones.

55
Example

LiCu(CH3)2
(98)
56
End of Chapter 18