Substitution at the α-carbon of carbonyl compounds: Chapter 22
or "How to functionalize a C next to a C=O"
Two major types of rxns of carbonyl compounds occur under basic conditions:
O
1) Substitution at the α-carbon (focus of Ch. 22)
(halogenation & alkylations)
Y
X
2) Condensation by reaction at the α-carbon (focus of Ch. 23)
Key factor in reactions:
C
H2
The nearby C=O of ketones, aldehydes, esters and
amides makes the α-hydrogens acidic and easy to
remove (see Table 22.1)
Two reasons:

Electron-withdrawing nature of the
carbonyl group

Resonance-stability of the conjugate
base (enolate)
Major feature of all α-C reactions and mechanisms: Keto-enol tautomerism
Section 22.1
 Most compounds are far more stable in the keto form
 When the enol forms, it’s reactive
 Phenols have more stable enol tautomers because they are aromatic
Mechanism of acid-catalyzed substitution (enol form):
H
H
O
H+
R
O
R
R
R
H
E+
O
O
R
R
R
R
H
H
E
AH
H
O
O
O
R
R
R
H
R
R
R
E
H
E
Key acid-catalyzed alpha-C substitution reactions:
A. Acid-catalyzed alpha-halogenation (22.3)
Br2, Cl2 or I2 can substitute at the α-carbon of an aldehyde or ketone
O
O
Br 2
H 3C
C
H2
CH3
H 3C
HOAc
CH
CH3
Br
Main uses:
1. Allows the α-carbon to be functionalized by SN2 substitutions
2. Provides route to α, β unsaturated ketones by elimination
B. Hell-Volhard-Zelinski (HVZ) reaction:
Carboxylic acids normally don’t enolize, so this reaction forms an acyl bromide
that does enolize and then undergoes α-bromination. Hydrolysis gives back the
carboxylic acid:
O
O
1. Br2, PBr 3
H 3C
C
H2
OH
2. H2O
H 3C
CH
Br
OH
Enolates
In the presence of strong base, an α-hydrogen can be removed to create a
carbanion that is resonance-stabilized through formation of an enolate species:
O
R
R
O
O
-:B
R
R
H
H
R
R
H
H
 Two nucleophilic sites are produced : the α-carbon and the oxygen.
Some strong bases: Lithium diisopropyl amide (LDA)
Sodium ethoxide (Na+ -OEt)
NaOH, NaNH2
Formation of an enolate by LDA:
In a based-catalyzed α-substitution:
• The nucleophile is a carbanion generated by deprotonation at α-C
• The electrophile can be varied for each reaction, to give variety of products.
Substitution reactions involving the enolate intermediate result in
replacement of acidic H by halogen or alkyl group
A) Halogenations:
22.6
B) Alkylations:
22.7
Iodoform reaction (base-catalyzed)
Direct α-alkylation of ketones, esters & nitriles
Malonic Ester Synthesis of substituted esters or carboxylic acids
Acetoacetic Acid synthesis of methyl ketones
A) Base-catalyzed halogenation:
Iodoform reaction: Classification test to identify a methyl ketone
O
O
CH3
H3C
O
-OH
I2, NaOH
CI 3
H3C
O
H3C
+ CHI 3
B) Alkylation: Base-catalyzed substitution of alkyl groups at the α-position
B1) Strong base (LDA) deprotonates the α-carbon of a ketone, ester or nitrile.
Enolate species is a good nucleophile, undergoes SN2 reaction with alkyl halides:
O
H3 C
C
C
H2
CH 3
O
O
LDA, THF
CH 3CH2 I
C
H 3C
CH 3
C
H
H 3C
O
C
H 3C
C
H
Steric hindrance can
determine what the
major product will be
H3 C
CH 3
C
H2
C
CH
CH 3
B2) Base-catalyzed diester alkylation: Activation of the “sandwiched” α-carbon
of diethyl malonate
A practical example: Synthesis of active barbiturates
O
Barbituric acid and its active derivatives are heterocyclic rings
that can be synthesized in 2 parts by condensation. The bottom half HN
comes from a diester, diethyl malonate; the top half from urea
NH
O
O
R
R'
The substituted barbiturates have sedative, hypnotic and anaesthetic
properties that vary with the chain length and structure of R groups
Amobarbital
R = ethyl
R’ = isoamyl
Pentobarbital
Phenobarbital
R = ethyl
R = ethyl
R = 2-pentyl
R = phenyl
Part 1 of the synthesis is α-alkylation of diethyl malonate:
O
O
C
C
C
H2
EtO
NaOEt
or K2 CO 3
O
O
C
C
EtO
OEt
C
H
O
O
Br(CH 2) 2CH(CH 3) 2
EtO
OEt
C
C
OEt
CH
H 2C
CH
C
H2
Part 2:
Repeat with bromoethane to put the ethyl group on
Part 3:
Condensation reaction with urea and strong base to complete ring
O
O
H 2N
NH 2
+
C
Et
HN
NH
C
C
EtO
NaOEt
EtOH
O
O
OEt
C 5H 11
O
O
Et
C 5H 11
CH 3
CH3
B3) Malonic ester synthesis: Base-catalyzed alkylation followed by hydrolysis
and decarboxylation is used to prepare longer carboxylic acids from alkyl halides
Overall reaction:
CH2(CO2Et)2
1. Base
2. R-X
3. H3O+
RCH2COOH + CO2 + EtOH
Example:
How can you prepare these using malonic ester synthesis?
B4) Acetoacetic ester synthesis is used to prepare methyl ketones from alkyl
halides
Using acetoacetic acid synthesis to prepare 2-pentanone:
How would you prepare:
How could you prepare the substituted ester shown?
Show the step-by-step mechanism, including resonance forms, and the final
product(s) of this base-catalyzed alkylation reaction:
O
H3C
H3C
CH3
C
C
CH3 H2
LDA/THF
CH3CH2I
Fill in the reagents needed to accomplish the transformation shown:
Reactions at the alpha-carbon, Part II:
Additions and condensations (Chapter 23)
1. Common and biologically relevant additions/condensations:
Formation of new C – C bonds with loss of water
A) Aldol Reactions:
Aldol Addition
23.1
(preparation of β-hydroxy aldehydes or ketones)
Aldol Condensation to form enones
(α, β unsaturated ketones)
Mixed Aldol
Intramolecular (cyclic) aldol
(yields primarily 5 or 6 membered rings)
23.3 – 23.4
23.5
23.6
B) Claisen Reactions: Claisen Condensation & Mixed Claisen Condensation
(preparation of β-keto esters or β-diketones) 23.7 - 23.8
Dieckmann cyclization
(forms cyclic β-keto esters)
23.9
2. Special addition & elimination reactions with synthetic utility
A) Michael Addition:
Conjugate addition of enolates to
23.10
α,β-unsaturated carbonyls ->1,5-dicarbonyls
B) Stork Enamine reaction:
Conjugate addition of enamines to
23.11
α,β-unsaturated carbonyls followed by hydrolysis
(forms 1,5-diketones)
1. Additions and condensations between aldehydes, ketones & esters
Review concepts:
• Carbonyl compounds have acidic H at the α-position
• Deprotonation at this position produces a resonance-stabilized
carbanion/enolate
• This reacts readily with electrophilic site of another molecule
Synthesis considerations:
• Focus on the functional groups that form in each reaction
• Keep track of which reagents supply which carbons and how they connect
• Condensations only require a catalytic amount of base
1A: Aldol addition: produces β-hydroxy aldehydes & ketones (“aldols”):
O
2
NaOH
C
H 3C
O
OH
H
H3C
C
H
C
H
C
H2
Mechanism:
The ensuing condensation (dehydration) of the aldol produces α, βunsaturated ketones
Example: The mixed aldol condensation of benzaldehyde and acetone
• Mixed aldols best when one reagent has no α-carbons
• One serves as nucleophile, the other as electrophile
• The dehydration step produces α,β-unsaturated product
O
O
CH
O
NaOH
C
+
H 3C
CH3
heat
or acid
C
H
H
C
+ H2O
C
CH3
1B: Claisen condensation: β-keto esters and β-diketones
Ester + ester produces β-keto esters (precursor of acetoacetic acid synthesis):
O
O
2
H 3C
C
O
H2
C
1. NaOCH2CH3
CH3
2. H3O +
O
C
C
H3C
C
H2
H2
O C CH3
Ketone + ester produces β-diketones:
O
+
C
H 3C
CH3
O
1. NaOCH3
C
2. H3O +
O
CH3
H3C
O
O
C
C
C
H2
+ CH3OH
The main difference between the aldol and Claisen reactions: Claisen reaction
involves elimination of a leaving group, regenerating C=O!
Intramolecular condensations:
Treating dicarbonyl compounds with base can promote cyclizations by aldol or
Claisen. Products form in a way that maximizes ring stability (favoring 5 or 6
membered rings).
Some examples:
Dieckmann cyclizations Claisen, works well with 1,6- or 1,7-diesters:
Aldol & Claisen reactions are very common in nature! Some biological
examples:
A. Aldol addition of two 3-carbon units B. Cross-linking of collagen protein
to make a 6-carbon unit occurs during as animals age: an aldol condensation:
gluconeogenesis:
C. Claisen condensation of thioesters (malonyl-CoA and acetyl-CoA) occurs in
fatty acid chain-building (biosynthesis)
2.
Special Additions/Eliminations
2A. Michael Additions of α, β−unsaturated carbonyl compounds
Recall that there are 2 positively charged sites in these species; they can undergo
both direct addition and conjugate addition:
In the Michael reaction, the nucleophile is an enolate species and conjugate
addition to the unsaturated structure produces a multifunctionalized carbonyl
compound:
 The products have the new group attached at the β-carbon
 The enolate can come from a β-diketone, β-diester or β-keto ester
 When the reactant is an ester, the base must have the same alkyl group
to avoid any change in the molecule if substitution occurs.
 The resulting 1,5-diketone can undergo a Robinson annulation
2B. Stork Reaction: Addition of enamines to α, β-unsaturated carbonyls to
produce
1,5-diketones
Ketones can be converted to enamines and used to alkylate α,β-unsaturated
carbonyl compounds because enamines have a carbanion resonance form:
R2 N
R2 N
The 3-step process results in formation of 1,5-diketones
(which are synthetically useful in cyclizations):
1. Enamine formation by reaction of ketone with a 2o amine
2. Michael addition of enamine to α, β-unsaturated carbonyl compound
3. Hydrolysis of the enamine regenerates the ketone group.
1,5-diketones prepared in this way may
undergo intramolecular aldol condensation
(annulation) forming a new 6-membered
ring
O
O
OH
NaOH
heat
O
O
Problems:
What enone product would form from aldol condensation in each of these
molecules?
What aldol condensation product would form from treatment of this compound with
base?
How might each compound be prepared using a Michael reaction? Show which
nucleophilic donor and electrophilic acceptor you would use (Table 23.1)
Fill in the missing reagents
Predict the products formed from a Michael addition, followed by intramolecular
aldol condensation (Robinson annulation):
1) 2,4-pentanedione + 2-cyclohexenone
2)