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Enols and Enolates

The α-Hydrogen Is Acidic

the anion is stabilizedby resonance

A carbon acid is a compound with a relatively acidichydrogen bonded to an sp3-hybridized carbon

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Enols and Enolates

structure

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enols and enolates are potential nucleophiles

• Ketone enol • Ketone enolate

tautomerism

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Enolates as nucleophiles

Acidity of α-Hydrogens

pKa ≈≈≈≈ 50pKa = 19

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stabilisation by delocalisation of the negative charge

pKa = 16pKa = 5

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Ketone vs Aldehyde enolates

pKa = 17pKa = 19

Diketone Enolates

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• Why is the hydrocarbon 1,3-cyclopentadiene so acidic?

pKa = 16

Enolate reactions

Michael reaction

aldol reaction

alkylation

halogenation

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α-Halogenation of Aldehydes and Ketones

mechanism

Step 3:An acid / base reaction. Here the

bromide ion is used to deprotonate

the oxonium ion.

Step 2:

Here the electrons from the oxygen

are used as they enhance the

nucleophilicity of the alkene, as a

result we end up with an oxonium ion

and a bromide ion.

Step 1:First, tautomerise the carbonyl to its

enol tautomer (mechanism not shown

here)

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Basic α-Halogenation of Aldehydes and Ketones

Mechanism of Basic α-Halogenation

Step 2:The nucleophilic enolate reacts

with the halide giving the

halogenated ketone and a bromide

ion.

Step 1:First, an acid-base reaction.

Hydroxide functions a s a base and

removes the acidic α-hydrogen giving the enolate.

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The Haloform reaction

Mechanism of the Haloform reaction

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Alkylation of Enolates

Mechanism of the Alkylation of Enolates

Step 2:The nucleophilic enolate attacks the alkyl halide

at the electrophilic carbon carrying the halogen

via an SN2 type process giving alkylated ketone

and a bromide ion.

Step 1:First, an acid-base reaction. Hydroxide functions

as a base and removes the acidic α-hydrogen giving the reactive enolate.

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Alkylation

• Enolate ion can be a nucleophile.

• Reacts with unhindered halide or

tosylate via SN2 mechanism.

O

H

H

O

H(i-Pr)2N

-Li

+

CH3 Br

O

H

CH3

=>

Stork Alkylation

• Milder alkylation method than using LDA.

• Ketone + 2° amine → enamine.

• Enamine is α-alkylated, then hydrolyzed.

O

H

H NH

H+

H

HHO

NH

+N

H

H+

N

H

CH3 Br

+N

H

N

H

CH3

H3O+

O

CH3

H

Br-

+ NH

H

+ =>

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Acylation via Enamines

Product is a β-diketone.

=>

The Aldol Condensation of Aldehydes

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Conjugation stabilizes the dehydrated product

Mechanism of the Aldol Condensation of Aldehydes

Step 3:

An acid-base reaction. The alkoxide deprotonates a

water molecule creating hydroxide and the β−hydroxyaldehydes or aldol product.

Step 2:The nucleophilic enolate attacks the aldehyde at the

electrophilic carbonyl C in a nucleophilic addition type

process giving an intermediate alkoxide.

Step 1:

First, an acid-base reaction. Hydroxide functions as a

base and removes the acidic α-hydrogen giving the reactive enolate.

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Mechanism of the dehydration of the Condensation product

Step 2:The electrons associated with the negative

charge of the enolate are used to form the

C=C and displace the leaving group,

regenerating hydroxide giving the

conjugated aldehyde.

Step 1:First, an acid-base reaction. Hydroxide

functions as a base and removes an acidic

α-hydrogen giving the reactive enolate.

The Aldol Condensation of Ketones

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Mixed Aldol Condensations

• Only one reactent can form an enolate.

• This means the other reactent lacks α-hydrogens

• One reactent is more electrophilic than the other and functions as

the electrophilic carbonyl component.

• In general, aldehydes are more reactive (electrophilic) than ketones

and will usually be the electrophile.

The Mixed Aldol Addition

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One product will be formed if one of the carbonyl

compounds does not have any α-hydrogen

Primarily one product can be formed by using LDA todeprotonate one of the carbonyl compounds

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Intramolecular Aldols

• The aldehyde will be the electrophile and the ketone the enolate.

• There two possible enolates (at C5 or C7).

• The more favourable ring size will the 5-membered ring.

Intramolecular Aldol Additions

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Enolates in Conjugated Systems

Enolates in Conjugated Systems

α,β-unsaturated aldehydes and ketones can potentially react with nucleophiles at

two sites : directly at the carbonyl C or the

end of the conjugated system

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1,2 vs 1,4

• In direct addition, the Nu attacks "directly" at the carbonyl C=O.

• this reaction is usually faster but the product is less stable (i.e. it is

the kinetic product).

• In conjugate addition, the Nu attacks the end of the conjugated

system at the end of the C=C (thermodynamic product).

Tautomerism of the 1,4-product

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Conjugate Addition reactions

• Conjugate or 1,4-addition tends to occur with nucleophiles that are weaker bases.

• Examples : thiols RSH, cyanide ion -CN, organocopper reagents R2CuLi, and enolates.

• Direct or 1,2-addition tends to occur with nucleophiles that are stronger bases.

• Examples : Organolithiums RLi, lithium aluminium hydride, LiAlH4 and Grignard reagents, RMgX.

• The product of conjugate addition is usually more stable (i.e. the thermodynamic product) as it still contains the strong C=O bond

Conjugate Addition reactions

Michael reaction

Organocuprates

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Conjugate Addition with Organocopper reagents

• Organolithium cuprates, R2CuLi are particularly useful for conjugate or 1,4-addition to α,β-unsaturated aldehydes and ketones.

• Lithium dialkylcuprates are formed from organolithium compounds

• Other organometallic reagents such as alkyl lithiums tend to undergo direct or 1,2-addition, while Grignard reagents may give mixtures of 1,2- and 1,4-addition depending on the system.

Mechanism of the Organocoprate Addition

Step 2: On acidic work-up, the enolate is protonated at the

α-C creating the more favourable carbonyl group.

Step 1: The nucleophilic C in the cuprate attacks the conjugated ketone at the electrophilic alkene C in a nucleophilic addition type process with the

electrons being pushed through to the

electronegative O, giving an intermediate enolate.

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The Michael Addition reaction

• Reagents: commonly bases such as NaOH or KOH.

• The first step is the formation of the enolate.

• Enolates tend to react with α,β-unsaturated ketones via conjugate addition.

• A conjugate addition with a carbanion nucleophile is

known as the Michael reaction or Michael addition.

Mechanism of the Michael Addition

Step 3: An acid-base reaction. The enolate deprotonates a

water molecule recreating hydroxide and the more

favourable carbonyl group.

Step 2: The nucleophilic enolate attacks the conjugated

ketone at the electrophilic alkene C in a nucleophilic addition type process with the electrons

being pushed through to the electronegative O,

giving an intermediate enolate.

Step 1: First, an acid-base reaction. Hydroxide functions as

a base and removes the acidic α-hydrogen giving the reactive enolate.

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The Robinson Annulation

• Forms bicyclic systems containing a substituted cyclohexenone system.

• These products are important systems in various natural products, for

example within steriods.

• "Annulation" means "building a ring"

• The reaction is named after Sir Robert Robinson.

• The sequence involves the following steps:

• Michael addition of an enolate on a conjugated ketone

• An intramolecular Aldol reaction

• An elimination of an alcohol to give a conjugated ketone

The Robinson Annulation

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Planning Aldol Syntheses

=>

Designing a Synthesis to Make New Carbon–Carbon Bonds

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Preparation of the Ester

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A Biological Aldol Condensation

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A Biological Claisen Condensation

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• Organic Chemistry, Carey

• Organic Chemistry, Bruice

• Organic Chemistry, Wade