Chapter 22 Notes Part 2

XXII. Chemistry of Enolates & Related Intermediates

A. Synthesis of -Dicarbonyls (1,3-Dicarbonyls)

1. Enamine Acylation / Iminium Ion Hydrolysis (Review)

Example:

2. Oxidation of Aldol Adducts (Review)

Example:

3. Claisen Condensation
The Claisen Condensation involves addition of an enolate to the carbonyl of an
ester. The resulting tetrahedral intermediate collapses to form a -dicarbonyl
product.
Example 1 and Mechanism:

Note: Deprotonation of the final product forms a stable enolate which prevents
the reverse process (addition to the ketone carbonyl and retro-Claisen) from
occurring.

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 Example 2 and Mechanism: Intramolecular Claisen (Dieckmann Condensation)

Note: This reaction is general when forming 5- or 6-membered rings.

4. Crossed Claisen Reactions

The Crossed Claisen Reaction (like the crossed-aldol) uses two different
carbonyl components.
Enolate: Can be derived from ketones or esters

Carbonyl Electrophile: Can be an acid chloride, anhydride, carbonate, or

different ester

Base: Depending on the electrophile used, bases can be strong (e.g. LDA) or
moderate (e.g. NaOMe). Moderate bases like NaOMe are usually not compatible
with acid chlorides, anhydrides, or carbonates since they can act as competitive
nucleophiles with the enolate.
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Example 1 and Mechanism: Use of one ester with no -protons.

Example 2 and Mechanism: Crossed Claisen with Ketone and Ester (both with
-protons)

Example 3 and Mechanism: Reaction with acid chloride

Note: The enolate must be generated using a strong base like LDA prior to
addition of the acid chloride. Bases like NaOMe can also add to the acid chloride
as a side reaction. This usually also applies to use of carbonates and anhydrides
(see below)
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 Example 4: Reaction with anhydride

Example 5: Reaction with carbonate

B. Reactions of -Dicarbonyls
-Dicarbonyls have very acidic a-protons and deprotonation leads to stabilized
enolates that can act as nucleophiles in a variety of addition reactions.

1. Malonic Ester Synthesis

Malonates are the general name given to -diesters (1,3-diesters). The central
carbon is easily alkylated and, following this, one of the esters can be removed
with acid and heating in a hydrolysis / decarboxylation process.
Example 1 and Mechanism:

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Example 2: Sequential alkylation / decarboxylation

Note: The -proton of the first alkylation product is slightly less acidic due to the
presence of the electron donating alkyl group. Consequently, a slightly stronger
base like t-BuOK is required.

Example 3: Double alkylation with dihalides / decarboxylation

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2. Acetoacetic Ester Synthesis
Enolates derived from acetoacetic esters (-ketoesters) can be alkylated in a
similar manner as malonates. Decarboxylation of the resulting alkylation
products yields a ketone.
Example 1: Alkylation / decarboxylation

Alternatively, such enolates can be acylated with acid chlorides. Decarboxylation

of the resulting acylation product yields 1,3-diketones (-diketones). A strong
base like NaH is generally employed to generate the enolate irreversibly (and
also since alkoxide bases react with acid chlorides). Polar solvents are required
to dissolve the polar enolate salt.
Example 2 and Mechanism: Acylation / decarboxylation

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C. Chemistry of -Unsaturated Carbonyls
Owing to their unique reactivity, -unsaturated carbonyls are frequently used
intermediates in organic synthesis. The conjugated alkene-carbonyl system
allows nucleophiles to add to either the carbonyl or the -carbon (via conjugate
addition).

1. Synthesis of -Unsaturated Carbonyls

a. Aldol Reaction (Review)
Example:

b. Selenation-Oxidation
This overall oxidation process begins with a-selenation of a ketone or aldehyde
followed by oxidation of the selenium atom and subsequent elimination.
Example 1 and Mechanism:

Example 2:

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2. Conjugate Addition (Michael Addition)
Addition of a nucleophile to the -position of an -unsaturated carbonyl is
called conjugate addition (or the Michael addition). In this context nucleophiles
are referred to as Michael donors and electrophiles as Michael acceptors.
In general, soft nucleophiles with delocalized anions (e.g. malonate anions)
make good Michael donors.
Example 1 and Mechanism: 1,4-addition

Common Michael Acceptors:

Common Michael Donors:

Note that hard nucleophiles like Grignard reagents add to the carbonyl.

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Example 2:

Example 3:

Example 4:

Example 5: Gilman Reagent vs Grignard Reagent

Example 6: Multistep synthesis

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3. The Robinson Annulation
The Robinson Annulation is a synthetic method that condenses ketone enolates
with Michael acceptors. The reaction begins with a Michael addition and the
resulting enolate reacts with the ketone in an intramolecular aldol condensation,
forming a ring (annulation).
Example 1 and Mechanism:

Example 2:

Example 3:

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