Enols and Enolates

1
Chapter 18

• Enols and Enolates

2
Terminology
?
?
?

• The reference atom is the carbonyl carbon.
• Other carbons are designated ?, ?, ?, etc. on
  the basis of their position with respect to the
  carbonyl carbon.
• Hydrogens take the same Greek letter as the
  carbon to which they are attached.

3
Alpha Halogenation of Aldehydes and Ketones


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.

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
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

6
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

7

• Lets look at the Mechanism of Enolization
• A. Acid Catalized
• B. Base Catalized

8
Enol Content
enol
keto

• percent enol is usually very small
• keto form usually 45-60 kJ/mol more stablethan
  enol

9
Enol Content
Acetaldehyde
K 3 x 10-7
10
2,4-Cyclohexadienone

• keto form is less stable than enol form
• keto form is not aromatic
• enol form is aromatic

11
1,3-Diketones(also called ?-diketones)
Example 2,4-pentanedione
(20)
(80)

• keto form is less stable than enol form

12
Enol form of 2,4-pentanedione
intramolecular hydrogen bond
103 pm
166 pm
H
O
O
133 pm
124 pm
C
C
H3C
C
CH3
134 pm
141 pm
H
CC and CO are conjugated
13
Acidity of ?-Hydrogen
H
14

• Discuss Mechanism of Base Catalized Enolate Ion
  Formation.

15
Acidity of ?-Hydrogen
16
?-Diketones are much more acidic
pKa 9
17
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.
18
Example
Br2, NaOH, H2O

CHBr3
H
(71-74)
19

• Chemical and Stereochemical Consequences of
  Enolization

20
Hydrogen-Deuterium Exchange

4D2O
KOD, heat

4DOH
21
Mechanism

22
Mechanism
23
Stereochemical Consequences of Enolization
H3O
50 R50 S
50 R50 S
100 R
H2O, HO
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
26
Aldol Addition




pKa 16-20
pKa 16

• 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?

27
Aldol Addition of Butanal
KOH, H2O
6C
28
Aldol Condensation
NaOH
29
Aldol reactions of ketones

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

30
Intramolecular Aldol Condensation
Na2CO3, H2O
heat
31
Intramolecular Aldol Condensation
Na2CO3, H2O
heat

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

32
NaOH

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

33
Mixed Aldol Reactions
NaOH

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

34
In order to effectively carry outa mixed aldol
condensation

• need to minimize reaction possibilities
• usually by choosing one component that cannot
  form an enolate

35

• formaldehyde and aromatic aldehydes cannot form
  an enolate ions
• and are reactive toward nucleophilic addition

36
Formaldehyde
K2CO3

water-ether
(52)
37
Aromatic Aldehydes

NaOH, H2O
30C
(83)
38
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

39
Acrolein
40
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

41
Dipole Moments
?
?
?
?
?

Butanal
trans-2-Butenal

• greater separation of positive and negative
  charge

42
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

43
Kinetic versus Thermodynamic Control

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

44

1,2-addition
1,4-addition
CO is stronger than CC
45
1,2-Addition

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

46
Example
1. THF2. H3O
47
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

48
Example
(93-96)
49
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
  .

50
Example
NaOHheat
not isolateddehydrates under reaction conditions
51
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.

52
Example

LiCu(CH3)2
(98)
53
Enolate Ions in SN2 Reactions

• Enolate ions are nucleophiles and react
  withalkyl halides.
• However, alkylation of simple enolates does not
  work well.
• Enolates derived from ?-diketones can
  bealkylated efficiently.

54
Example
K2CO3

CH3I
CH3CCHCCH3
(75-77)