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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
Enolate Reactions: AlkylationEnolate (nucleophile) + alkyl halide (electrophile) SN2 reaction
Example:
New C-C bondnext to C=O
O
1. LDA
2. CH3I
O
CH3
Mechanism:
O O
CH3H N(iPr)2
O H3C I
SN2
O
CH3C
CH3H3C
Enolate Reactions: AlkylationEnolate (nucleophile) + alkyl halide (electrophile) SN2 reaction
•Enolate alkylation must meet usual SN2 requirements...
O
+ (CH3)3C-I
SN2 E2
O
+ CH2C CH3
CH3
Nuc + R3C–LGSolvent
Nuc–CR3 + LG
Enolates are usually
_________ nucleophiles
Enolate solventsOK for SN2
Not _______ Depends on electrophile
Example:
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 4
O
H OH
O
Ph H
O O
Ph
OH H OH O
Ph
OH
+ HO
Enolate Reactions: The Aldol ReactionEnolate + ___________________________
Another electrophileProduct?Aldehyde or ketone
Example: Predict product byworking out mechanism
Mechanism:•Strong base present so consider enolate pathways before addition/substitution
•PhCHO cannot form enolate
Keq = __________
Aldehyde more / less
electrophilic than ketone
O
Ph H
O
+NaOH
H2O
Tetrahedral adduct...
Enolate Reactions: The Aldol ReactionO
H OH
O
Ph H
O O
Ph
OH H OH O
Ph
OH
+ HO
Is further reaction possible?
•Strong base present
•O=C-C-H present
General rule: RO- can leave when...
...ejected from oxyanionic tetrahedral adduct:
...E2 leads to C=C-C=O conjugation:
O
Ph
HO
H OH
O
Ph
+ H2O + HO
OCH3O O+ OCH3
O
Ph
HO
H OH
O
Ph
+ H2O + HO
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 5
Enolate Reactions: The Aldol Reaction
β-Hydroxyketone
Aldol reaction: Reaction of aldehyde/ketone with aldehyde/ketone enolate to give β-hydroxyaldehyde or β-hydroxyketone.
•Aldol from aldehyde alcohol.
Ketone/ketone aldol: Aldehyde/aldehyde aldol:
Overall reaction:
Also possible:
O NaOH
H2O
O
NaOHO
+
Ph H
ONaOH
H2O
OHO
PhH2O
O
Ph
O
+
Ph H
ONaOH
H2O
OHO
PhH2O
O
Ph
H3O+
αβ
H
O
H
ONaOH
H2O
Enolate Reactions: The Claisen Condensation
Mechanism:•Strong base present so consider enolate pathways before addition/substitution
Product?Ester enolate + ester
Example:Predict product by
working out mechanismOCH3
O1. NaOCH3
2. H3O+???
Enolates reactwith electrophiles
Tetrahedraladduct...
CH3O
H OCH3
O
CH3O
O
OCH3
O
CH3O
O OCH3O
CH3O
O OKeq _____
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 6
Enolate Reactions: The Claisen Condensation
But we're not done yet... Strong base + acidic proton!
CH3O
H OCH3
O
CH3O
O
OCH3
O
CH3O
O OCH3O
CH3O
O O
pKa 11Why this pKa less than
ketone but more than ester?
Keq > 1
CH3O
O O
H OCH3
CH3O
O O
H OH2
CH3O
O O
This deprotonationis unavoidable.
Enolate Reactions: The Claisen CondensationOverall reaction:
OCH3
O1. NaOCH3
2. H3O+OCH3
O O
β-ketoester
Condensation reaction: Two molecules combine to form a larger molecule with loss ofa small molecule such as H2O, CH3OH, or NH3.
•Can also be intramolecular (i.e., within one molecule).
•Condensation usually refers to formation of carbon-carbon bonds.
Claisen condensation: Condensation of two esters to form a β-ketoester.
Rainer Ludwig Claisen (1851-1930)
•Published Claisen condensation in 1881
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 7
Enolate Reactions: The Claisen CondensationIntramolecular Claisen condensation Intramolecular = within the molecule
•Excellent reaction to build five-membered and six-membered rings
Student exercises: -- Work out the complete mechanism
-- What reactants make a six-membered ring?
-- Why use NaOCH3 instead of NaOH?
CH3O
O
OCH3
O
1. NaOCH3
2. H3O+
O
OCH3
O
•Called Dieckmann condensation Walter Dieckmann (1869-1925)
Enolate Reactions: Reactivity
What other carbonyl compounds will enolates react with?
Acid chlorideThioesterAnhydride
Aldehyde Ketone Ester Amide Carboxylate
•There is no amide or carboxylate version of the aldol and Claisen reactions.
Enolates, Enols, and Enamines Part 2 Lecture Supplement -- Page 8
What Electrophile Reacts with the Enolate?Example:
Electrophile = starting ketoneSelf-condensation occurs
Electrophile = PhCH2BrSelf-condensation avoided
ONaOH
O
...but...O
1. LDA
2. PhCH2Br
O
Ph
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
