Chem A225 Notes Page 124 Chapter 22: Enolate … the trend that replacing a ketone with an ester...

Chem A225 Notes 24

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


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.



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.



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).



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:



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:



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)



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

Chem A225 Notes Page 124 Chapter 22: Enolate … the trend that replacing a ketone with an ester...

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