Enolates, Enols, and Enamines Part 2 Rainer Ludwig Claisen OCH 3 O 1. NaOCH 3 2. H 3 O + OCH 3 O O Walter Dieckmann CH 3 O O OCH 3 O 1. NaOCH 3 2. H 3 O + O OCH 3 O Part 1 Summary H Base O O O Enolate •pK a important to determine how much enolate formed, which base to use pK a 19 H O pK a 9 H O O pK a 25 H 3 CO H O Enolate has two resonance contributors Enolate has three resonance contributors Enolate destabilized by OCH 3 electron donation Easier to form than ketone enolate Harder to form than ketone enolate Therefore Therefore Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 1
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Enolates, Enols, and EnaminesPart 2
Rainer Ludwig Claisen
OCH3
O1. NaOCH3
2. H3O+OCH3
O O
Walter Dieckmann
CH3O
O
OCH3
O
1. NaOCH3
2. H3O+
O
OCH3
O
Part 1 Summary
H Base
O OO
Enolate
•pKa important to determine how much enolate formed, which base to use
pKa 19H
O
pKa 9H
OO
pKa 25
H3CO
H
O
Enolate has tworesonance contributors
Enolate has threeresonance contributors
Enolate destabilizedby OCH3 electron donation
Easier to formthan ketone enolate
Harder to formthan ketone enolate
ThereforeTherefore
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 1
Enolate Formation: A Potential ProblemProblem: Strong base is also usually strong nucleophile...
How to avoid addition, and get enolate formation only?
HO- is a base
HO- is a nucleophile
CH3O
O
+ HO
CH3O
O
CH3O
OHO
Competing pathways
Enolate Formation: A Potential ProblemHow to avoid addition, and get enolate formation only?
•Reduce nucleophilicity? Strong base usually also strong nucleophile
•Steric effects?
H
OBase/Nuc
Less hindered than C
More hindered than H
•Therefore use sterically hindered strong base to minimize attack at C=O
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 2
•LDA is a very strong base; equilibrium favors... enolate ester Keq ~ _________
Enolate Formation: A Potential ProblemSterically Hindered Base Minimizes Attack at C=O
•LDA favors deprotonation instead of addition
Lithium diisopropyl amideLDA
Li+ -N(iPr)2
N
Li
CH3O
O
H N(iPr)2
CH3O
O
+ H N(iPr)2
pKa 25 pKa 36
1011
Not formed
N
OCH3O
Example: Use of LDA to form ester enolate
What is an Enolate Good For?Now that I have an enolate, what do I do with it?
Enolate is a nucleophilesuggests
Less significant contributor:FC on carbon (EN = 2.5)
More significant contributor:FC on oxygen (EN = 3.5)
R
O
•Resonance suggests multiple spots to form new bonds
•Enolates accept most electrophiles at carbon
•Enolates useful to form new carbon-carbon bonds
R
O
Elec
R
O
Elec
Elec
R
OElec
Negative formal charge
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 3
Clues:•Base: HO-/CH3O- = weaker bases; not all C=O converted to enolate LDA = strong base; all C=O converted to enolate
•Electrophile: Is a second electrophile (i.e. PhCH2Br) present in addition to C=O compound? Amides and carboxylates immune to attack by enolate
•In general: When base = RO-, self-condensation possible When base = LDA, self-condensation usually avoided If second electrophile shown, self-condensation is avoided If no second electrophile is shown, self-condensation is intended
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 9