Enolates, Enols, and Enamines
Part 1
O
O
NaOH
+
Ph
H
O
OH
H2O
O
NaOH
Ph
H2O
Ph
Similar Structures cause Similar Reactions
Reading: OCATSA Chapter 27
Name
Enolate
Resonance contributors
O
O
Resonance hybrid
δ−
O
δ−
α
Enol
alkene + alcohol
Enamine
alkene + amine
HO
R2N
HO
δ+
HO
R2N
δ+
R2 N
β
Nucleophilic
at β-carbon
δ−
δ−
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 1
Enolates: Formation
Recall the three C=O group fates:
•Nucleophilic attack at carbon
Used extensively in C=O
addition and substitution reactions
•Accept electrophile (usually H) at oxygen
O
O
O
•Form enolate:
H
Base
Enolate
Important issues:
•Which O=C-C-H is most acidic (removed first)?
•What base to use?
•How much enolate is formed?
Relative Acidity of H-C-C=O
O
O
Example:
O
O
+
Base
+
Which enolate is formed?
OCH3
Most acidic
H-C-C=O
comes from
indicated by
Lowest
pKa
Conjugate acid
most readily
deprotonated
comes from
Most stable
enolate
Example: H2SO4 pKa -9; H2O pKa 15.7
Review: --OCATSA chapter 9
--Tutorials on course web site
--Chem 14C notes
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 2
Relative Acidity of H-C-C=O
Ketones
Example: A ketone and its enolate
O
O
+
HO
+
H2O
pKa 15.7
Stronger acid
pKa 19
Weaker acid
Equilibrium position?
•Acid/base equilibrium favors weakest (most stable) acid and weakest (most stable) base
Keq < 1 (more ketone than enolate)
Keq > 1 (more enolate than ketone)
•Keq ~ 10(pKa right acid – pKa left acid) = 10(15.7 – 19) = 10-3.3
•pKa values do not need to be memorized, but can be useful to know
•Enolate is often drawn as its most stable resonance contributor
Relative Acidity of H-C-C=O
β-Diketones
O
O
O
O
+ CH3OH
+ CH3O
Keq ~
Keq < 1 (more diketone than enolate)
O
Keq > 1 (more enolate than diketone)
O
O
O
O
O
β-diketone enolate:
O
O
Ketone enolate:
More extensive delocalization?
Most stable enolate?
Most acidic?
Ketone enolate
Ketone enolate
Ketone
β-diketone enolate
β-diketone enolate
β-diketone
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 3
Relative Acidity of H-C-C=O
Esters
O
O
+
CH3O
+
CH3O
CH3OH
CH3O
Keq ~
Keq < 1 (more ester than enolate)
O
Keq > 1 (more enolate than ester)
O
O
δ−
Ketone enolate:
δ−
O
O
O
O
Ester enolate:
CH3O
δ+
CH3O
CH3O
CH3O
Largest δ− charges?
Most stable enolate?
Most acidic?
Ketone enolate
Ketone enolate
Ketone
Ester enolate
Ester enolate
Ester
δ−
δ−
Relative Acidity of H-C-C=O
O
O
O
O
+
Base
+
OCH3
pKa
19
O
9
O
Which enolate is formed?
•Most acidic proton removed first
25
O
O
CH3O
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 4
Enolate Formation: A Potential Problem
Problem: Strong base is also usually strong nucleophile...
O
HO- is a base
CH3O
O
+ HO
Competing pathways
CH3O
O
HO- is a nucleophile
OH
CH3O
How to avoid addition, and get enolate formation only?
Enolate Formation: A Potential Problem
How to avoid addition, and get enolate formation only?
•Reduce nucleophilicity? Strong base usually also strong nucleophile
•Steric effects?
Less hindered than C
H
Base/Nuc
O
More hindered than H
•Therefore use sterically hindered strong base to minimize attack at C=O
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 5
Enolate Formation: A Potential Problem
Sterically Hindered Base Minimizes Attack at C=O
Lithium diisopropyl amide
LDA
Li+ -N(iPr)2
Li
N
Example: Use of LDA to form ester enolate
CH3O
O
O
O
+
CH3O
H
H
N(iPr)2
N
CH3O
N(iPr)2
pKa 36
pKa 25
Not formed
•LDA favors deprotonation instead of addition
1011
ester Keq ~ _________
•LDA is a very strong base; equilibrium favors... enolate
What is an Enolate Good For?
Now that I have an enolate, what do I do with it?
suggests
Negative formal charge
Less significant contributor:
FC on carbon (EN = 2.5)
O
Elec
O
Elec
R
R
Elec
More significant contributor:
FC on oxygen (EN = 3.0)
O
Elec
R
O
R
•Resonance suggests multiple spots to form new bonds
•Enolates accept most electrophiles at carbon
•Enolates useful to form new carbon-carbon bonds
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 6
Enolate Reactions: Alkylation
SN2 reaction
Enolate (nucleophile) + alkyl halide (electrophile)
O
New C-C bond
next to C=O
O
1. LDA
Example:
CH3
2. CH3I
O
O
Mechanism:
H
H3C
O
I
CH3
N(iPr)2
SN2
Enolate Reactions: Alkylation
SN2 reaction
Enolate (nucleophile) + alkyl halide (electrophile)
•Enolate alkylation must meet usual SN2 requirements...
Not _______
Nuc + R3C–LG
Depends on electrophile
Nuc–CR3 + LG
Solvent
Enolate solvents
OK for SN2
Enolates are usually
_________ nucleophiles
O
Example:
O
+ (CH3)3C-I
H3C
CH3
O
CH3
C
CH3
+
C
H2C
S N2
CH3
E2
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 7
Enolate Reactions: The Aldol Reaction
Enolate + ___________________________
Product?
Another electrophile
O
O
Example:
NaOH
+
Ph
H
H2O
Predict product by
working out mechanism
Mechanism:
•Strong base present so consider enolate pathways before addition/substitution
•PhCHO cannot form enolate
Keq = __________
O
O
O
Ph
H
OH
O
H
Aldehyde more / less
H
O
H
OH
O
OH
Ph
Ph
Tetrahedral adduct...
+ HO
electrophilic than ketone
•HO- is ________________ and __________________.
Enolates, Enols, and Enamines Part 1 Lecture Supplement -- Page 8