chem a225 notes page 124 chapter 22: enolate … the trend that replacing a ketone with an ester...
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Chem A225 Notes Page 124
Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.
Chapter 22: Enolate Reactions (Part Two)
I. Trends in Acidity of Carbonyl Compounds
Esters are less acidic than ketones or aldehydes. Why? Compare the stabilities of their conjugate bases:
-Dicarbonyls are much more acidic than simple esters, aldehydes, or ketones.
Note the trend that replacing a ketone with an ester makes the structure less acidic (larger pKa).
Dicarbonyl Name Structure pKa
-diketone 9
-keto ester 11
-diester 13
R C CH2
O
C
O
R
R C CH2
O
C
O
OR
RO C CH2
O
C
O
OR
Chem A225 Notes Ch 22: Enolate Reactions (Part Two) Page 125
Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.
Why are -dicarbonyls so acidic? More resonance to stabilize their conjugate bases (remember, more stable conjugate base makes a stronger acid).
-Dicarbonyls can be almost completely deprotonated using hydroxide or alkoxide bases (instead requiring very strong bases such as LDA). These are useful conditions in biological systems.
Chem A225 Notes Ch 22: Enolate Reactions (Part Two) Page 126
Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.
II. Condensation of Ester Enolates: The Claisen Condensation
A. Observed Reaction
The alkyl group (R) on the ester must be the same as the alkyl group (R) on the alkoxide base; if they are different, we can get undesired transesterification.
Usually the two esters are the same (similar to aldol condensation).
B. Mechanism
The production of the Claisen Condensation is a -dicarbonyl, which is a much stronger acid than the ester reactant. When the product is formed during the reaction, it is immediately deprotonated by the base (RO–) that is used in the reaction. This consumes an equivalent of base, and cannot be prevented.
Chem A225 Notes Ch 22: Enolate Reactions (Part Two) Page 127
Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.
C. Crossed Claisen Condensation
The crossed Claisen condensation works best when one of the esters has no acidic -hydrogens (similar to a crossed aldol):
A similar crossed Claisen condensation occurs between a ketone and an ester. The ketone is the stronger acid, so it is deprotonated and acts as the donor:
D. Intramolecular Claisen Condensation (Dieckmann Condensation)
Can be used to form 5- or 6-membered rings (doesn’t work well for other sizes).
Chem A225 Notes Ch 22: Enolate Reactions (Part Two) Page 128
Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.
III.Malonic Ester and Acetoacetic Ester Synthesis
Observed Reaction
Effectively, this reaction replaces the —COOEt part of the reactant with an SN2 compatible R group.
Mechanism:
Chem A225 Notes Ch 22: Enolate Reactions (Part Two) Page 129
Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.
IV.Decarboxylation of -Keto Acids
-Keto acids decarboxylate (lose CO2) readily when heated.
Observed Reaction
Mechanism (6-membered ring transition state)
V. Addition to ,-Unsaturated Carbonyls
A. 1,2 vs. 1,4 Addition (Conjugate Addition)
An ,-unsaturated carbonyl compound has a carbon-carbon double bond conjugated with the C=O pi bond. Resonance delocalizes the + charge that is on the C=O carbon:
Chem A225 Notes Ch 22: Enolate Reactions (Part Two) Page 130
Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.
Nucleophiles can add to either the C=O carbon or the beta carbon. Addition to the C=O carbon is called 1,2-addition:
Addition to the beta carbon is called 1,4-addition or conjugate addition:
The properties of the nucleophile determine where it will prefer to add.
Nucleophiles with low polarizability prefer to add 1,2. Examples include ROH, H:– (from LiAlH4), R:–MgX+ and R:– Li+.
Nucleophiles with high polarizability prefer to add 1,4. Examples include sulfur nucleophiles (RSH), cuprates (R2CuLi), and enolates.
B. Conjugate Addition of Alkyl Cuprates
Observed Reaction
Formal Mechanism (actual mechanism probably involves radicals)
Chem A225 Notes Ch 22: Enolate Reactions (Part Two) Page 131
Lecture Notes © 2017 Dr. Thomas Mucciaro. All rights reserved.
The enolate intermediate can be alkylated:
C. Michael Addition: Conjugate Addition of Enolates
Observed Reaction
Michael Addition of enolates produces 1,5-dicarbonyls.
Mechanism
Examples
Chem 225 Notes Ch 22: Enolate Reactions (Part Two) Page 127
Lecture Notes © 2003-2016 Dr. Thomas Mucciaro. All rights reserved.
D. Robinson Annulation (Michael Addition followed by Aldol Condensation)
Annulation: ring forming reaction
Observed Reaction
Mechanism