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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
7
• Why is the hydrocarbon 1,3-cyclopentadiene so acidic?
pKa = 16
Enolate reactions
Michael reaction
aldol reaction
alkylation
halogenation
8
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)
9
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.
11
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.
12
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
+ =>
14
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.
15
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
16
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
17
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
20
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
21
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
22
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
23
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.
24
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.
25
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