Chapter 18 Lecture 1 Enols
I.
O
Enolate Ions
C
CH
a
A.
Carbonyl Reactivity
1) Nucleophilic carbonyl oxygen
2) Electrophilic carbonyl carbon
3) a-carbon containing acidic a-protons (the subject of this chapter)
B.
Acidity of Aldehydes and Ketones
1) pKa of protons alpha to an aldehyde or ketone carbonyl = 19-21
a) Ethene pKa = 44
b) Ethyne pKa = 25
c) Alcohol pKa = 15-18
2)
Strong bases can remove a-hydrogens to produce an Enolate Ion
O
C
-
C
H
B
O
O
C
C
C
Enolate Ion
C
3)
C.
Why are carbonyl a-protons acidic?
a) The conjugate base is stabilized by the enolate ion resonance structures
b) The d+ carbon of the carbonyl destabilizes the a C—H bond
Formation of Enolate Ions
1) LDA (lithium diisopropyl amide) or other strong bases are used
2) Aprotic solvents are used to prevent solvent deprotonation
O
H
H
H
H +
CH
H3C
3)
d-
O
H3C
NLi
THF
H
H
2
H3C
H
+
CH
H3C
NH
2
Enolate Resonance Hybrid
a) The a-carbon and the oxygen of an enolate ion are both nucleophilic
O
C
C d-
b)
Ambident = “two-fanged” = a species that can react at 2 different sites to
give 2 different products
O
O
CH3
protonation
tautomerization
Keto-Enol Equilibria
A.
Ketone—Enol Tautomerization
1) This reaction is reversible, and the extent of reaction depends on conditions
2) Base-catalyzed Enol-Keto Equilibration
a) Base removes proton from the enol
b) The mechanism is the reverse of the original enolate formation
O
C
H
The carbon atom is the normal site of reaction by SN2. This type of
reaction is called alkylation or C1-alkylation of the enolate ion.
The oxygen atom is the normal site of protonation, forming an enol,
which will tautomerize to the original ketone.
b)
II.
O
H+, H2O
CH3I, THF
alkylation
a)
OH
O
C
enol
H
O
B
C
C
O
C
enolate ion
C
O
BH
C
C
H keto
2)
O H
Acid Catalyzed Enol-Keto Equilibration
a) Protonation occurs at the double bond
b) Resonance stabilized C is next to O
c) Protonated carbonyl deprotonates to give the keto form
+
H
H
H
C C
O H
C C
H
O
-H+
O
C C
C C
H
keto
enol
3)
4)
5)
B.
Both reaction are fast if the catalyst (B- or H+) are present
Keto form is usually dominant
Keto to enol tautomerization mechanisms are the reverse of those above
Effects of Substituents on Keto-Enol Equilibria
1) Ketone donating substituents stabilize keto form
2) Aldehyde lack of donating substituents pushes equilibria toward enol form
O
OH
H CH2 C
H2C
H
-7
K = 6 x 10
o
C
G = +8.5 kcal/mol
O
H CH2 C
H
OH
H2C
CH3
-9
K = 5 x 10
C
CH3
G = +11.3 kcal/mol
o
C.
D.
Deuteration of Carbonyl a-Carbons
1) Dissolving an aldehyde or ketone in D2O, DO- (or D+) replaces all of the aHydrogens with Deuteriums
O
O
D2O
CH3 CD2 C CD3
CH3 CH2 C CH3
OD
2)
Even though the keto form dominates, a small % is always tautomerizing to
the enol. Over time, reprotonation at C gives the fully deuterated product.
3)
Reaction can be followed by 1H NMR as a-H signal disappears
Interconversion of a-C stereochemistry
1) Keto-Enol tautomerization proceeds through an achiral intermediate
O
O
O
CH2CH3
CH3
cis, crowded
KOH
CH2CH3
CH3
planar enol
CH2CH3
CH3
trans, less crowded
2)
Loss of optical activity occurs under basic or acidic conditions
O
O
B
C
C C CH3
H
H3C
O
C CH3
H3C
H3C
C C CH3
H
R,S-racemic mixture
S-enantiomer
III. Halogenation of Aldehydes and Ketones
A.
Acid-Catalyzed a-Halogenation of Ketones and Aldehydes
1)
In acidic conditions, only one halogen is able to add
O
CH3 C CH3
2)
O
Br2, HOAC
o
H2O, 70 C
BrCH2 C CH3
+ HBr
The reaction rate is independent of X2 concentration, suggesting that the rate
determining step depends only on the carbonyl compound
3)
Mechanism of acid catalyzed a monohalogenation
OH
O
+
H
CH3 C CH3
keto
BrCH2 C
OH
CH2 C
CH3
-H
Br Br
CH3
O
+
BrCH2 C
enol
OH
BrCH2 C
4)
O
C
C
H
keto
CH3
Why does the reaction stop after only one halogenation?
a) Mechanism requires enolization
b) Electron withdrawing Br prevents protonation needed in first step
H
+
H
H
C
O
C
H
C
O
C
H
-H+
O
C
C
enol
O
Br CH2 C
CH3
O is no longer basic enough
To attack proton. Enolization
Can’t happen.
H
CH3
B.
Base Mediated Halogenation of a-Carbon Goes to Completion
1) Mechanism
O
C C
B
2)
C C
C C
C C
H keto
O
O
O
Br
enolate ion
Br
Br
Electron Withdrawing Br increases a-Hydrogen acidity, favoring
complete bromination of all a-Carbons
O
Br CH2 C
CH3
3)
O
R
C CH3
The Iodoform test for Methyl Ketones is base catalyzed halogenation
I2, HO
O
O
-
R
C CI3
-
OH
R
C OH + HCI3
Iodoform
Yellow solid
IV. Alkylation of Aldehydes and Ketones
A.
Alkylation of Ketones Using NaH
1) Ketones with only one a-Hydrogen are alkylated in high yield
a) Example:
O
O
C CH(CH3)2
b)
1. NaH, benzene, 
2. CH3CH2Br
CH2CH3
NaH is a strong base yielding enolate ion when reacted with carbonyls
O
C
88% yield
C C(CH3)2
O
O
C(CH3)2
C
+ -
Na H
H
C(CH3)2
CH3CH2Br
C
SN 2
CH2CH3
enolate
2)
Polyalkylation occurs if multiple a-H’s are present
O
H
H
O
O
1. NaH
2. CH3I
+
27%
H
CH3
C(CH3)2
38%
CH3
CH3
3)
O
Unsymmetric Ketones give multiple products
O
H
CH3 1. NaH
2. CH3I
H
H
O
H
CH3
H
CH3
+
H3C
CH3
H
H
53%
36%
B.
Enamine Route to Ketone/Aldehyde Alkylation
1) Enamine formation makes C=C bonds electron rich by resonance
2) The nucleophilic a-Carbon can then attack electrophiles
H
O
CH3CH2CCH2CH3 +
N
OH
CH3CH2
C
-H2O
N
CH3CH
Enamine
azacyclopentane
C
N
CH2CH3
N
CH2CH3
CH2CH3
CH3CH
C
CH3CH
C
N
CH2CH3
CH3I
CH3
CH3CH
C
N
CH2CH3
3)
CH3
CH3CH
The amine is removed from the alkylated product by acid to give the
alkylated ketone or aldehyde
I-
CH3
H+, H2O
CH3CH
N
C
O
+
C
HN
CH2CH3
CH2CH3
Iminium Salt
4)
The Enamine Alkylation Route is Preferred
a)
No multiple alkylations
b)
Works on Aldehydes and Ketones
O
(CH3)2CHCH
1. azacyclopentane
2. CH3CH2Br
+
3. H , H2O
O
(CH3)2CCH
CH2CH3