CN>Chapter 22CT>Carbonyl Alpha-Substitution
ReactionsElectrophilic substitution reactions of
carbonyl-containing compounds
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The Position
• The carbon next to the carbonyl group is designated as being in
the position, hence called the alpha () carbon
• Electrophilic substitution occurs at this position through either
an enol or enolate ion
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Alpha Substitution
• Alpha substitution is the substitution (in most cases) of one of
the hydrogens attached to the alpha-carbon for an
electrophile.
• The reaction occurs through an enol/enolate ion
intermediate.
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•Many reaction schemes make use of carbonyl - substitution
reactions
•These reactions are one the few general methods for making C-C
bonds
• larger molecules can be synthesized from smaller precursors
•Other functional can be introduced into the product molecule
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Condensation with an Aldehyde or Ketone
• The enolate ion attacks the carbonyl group to form an
alkoxide
• Protonation of the alkoxide gives the addition product: a b-
hydroxy carbonyl compound
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Keto–Enol Tautomerism
• A carbonyl compound with a hydrogen atom on its carbon rapidly
equilibrates with its corresponding enol
• Compounds that differ only by the position of a moveable proton
are called tautomers
• Can be catalyzed either by an acid or a base
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•Tautomerization is an interconversion of isomers that occur
through the migration of a proton and the movement of a double
bond.
•Tautomers are not resonance form.
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• Resonance forms are representations of contributors to a single
structure
• Tautomers interconvert rapidly while ordinary isomers do
not
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Enols
• The enol tautomer is usually present to a very small extent and
cannot be isolated
• However, since it is formed rapidly, it can serve as a reaction
intermediate
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Acid-Catalyzed Tautomerism
• In acid, a proton is moved from the -carbon by first protonating
oxygen and then removing a proton from the carbon.
•Brønsted acids catalyze keto-enol tautomerization by protonating
the carbonyl and activating the protons
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Base–Catalyzed Tautomerism
• In the presence of strong bases, ketones and aldehydes act as
weak proton donating acids.
• A proton on the carbon is abstracted to form a resonance-
stabilized enolate ion with the negative charge spread over a
carbon atom and an oxygen atom.
• The equilibrium favors the keto form over the enolate ion.
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Formation and Stability of Enolate Ions
•The equilibrium mixture contains only a small fraction of the
deprotonated, enolate form.
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Racemization
• For aldehydes and ketones, the keto form is greatly favored at
equilibrium.
• If a chiral carbon has an enolizable hydrogen atom, a trace of
acid or base allows that carbon to invert its configuration, with
the enol serving as the intermediate. This is called
racemization.
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The Mechanism of Alpha-Substitution Reactions
• Enols behave as nucleophiles and react with electrophiles because
the double bonds are electron-rich compared to alkenes
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General Mechanism of Addition to Enols
• When an enol reacts with an electrophile the intermediate cation
readily loses the OH proton to give a substituted carbonyl
compound
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Alpha Halogenation of Aldehydes and Ketones • Aldehydes and ketones
can be halogenated at their
positions by reaction with Cl2, Br2, or I2 in acidic solution
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• The keto tautomer loses a proton
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Propose a mechanism for the acid-catalyzed conversion of
cyclohexanone to 2-chlorocyclohexanone.
Under acid catalysis, the ketone is in equilibrium with its enol
form.
The enol acts as a weak nucleophile, attacking chlorine to give a
resonance -stabilized intermediate.
Loss of a proton gives the product.
Solved Problem
Evidence for the Rate-Limiting Enol Formation
• The rate of halogenation is independent of the halogen's identity
and concentration
• In D3O+ , the H’s are replaced by D’s at the same rate as
halogenation
• This is because the barrier to formation of the enol goes through
the highest energy transition state in the mechanism
19Rate = k [Ketone][H+]
Elimination Reactions of -Bromoketones
• -Bromo ketones can be dehydrobrominated by base treatment to
yield ,b-unsaturated ketones
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Base-Catalyzed Halogenation Mechanism
• The base-promoted halogenation takes place by a nucleophilic
attack of an enolate ion on the electrophilic halogen
molecule.
• The products are the halogenated ketone and a halide ion.
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Multiple Halogenations
• The -haloketone produced is more reactive than ketone because the
enolate ion is stabilized by the electron- withdrawing
halogen.
• The second halogenation occurs faster than the first.
• Because of the tendency for multiple halogenations this
base-promoted halogenation is not widely used to prepare
monohalogenated ketones.
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O
H
Haloform Reaction
•A methyl ketone reacts with a halogen under strongly basic
conditions to give a carboxylate ion and a molecule of
haloform.
•The trihalomethyl intermediate is not isolated.
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Mechanism of Haloform Formation
• The trihalomethyl ketone reacts with hydroxide ion to give a
carboxylic acid.
• A fast proton exchange gives a carboxylate ion and a
haloform.
• When Cl2 is used, chloroform is formed; Br2 forms bromoform ; and
I2 forms iodoform.
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Propose a mechanism for the reaction of 3-pentanone with sodium
hydroxide and bromine to give 2-
bromo-3-pentanone.
In the presence of sodium hydroxide, a small amount of 3-pentanone
is present as its enolate.
The enolate reacts with bromine to give the observed product.
Solved Problem
Solution
Alpha Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii
(HVZ) Reaction
• Carboxylic acids do not react with Br2 (unlike aldehydes and
ketones)
• They are brominated by a mixture of Br2 and PBr3 (Hell–
Volhard–Zelinskii reaction)
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Mechanism of Bromination
• PBr3 converts -COOH to –COBr (Acid halide), which can enolize and
add Br2
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Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation • Carbonyl
compounds can act as weak acids (pKa of acetone
= 19.3; pKa of ethane = 60)
• The conjugate base of a ketone or aldehyde is an enolate ion -
the negative charge is delocalized onto oxygen
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Reagents for Enolate Formation
• Ketones are weaker acids than the OH of alcohols so a more
powerful base than an alkoxide is needed to form the enolate
• Sodium hydride (NaH) or lithium diisopropylamide [LiN( i- C3H7)2]
are strong enough to form the enolate
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Lithium Diisopropylamide (LDA)
• LDA is from butyllithium (BuLi) and diisopropylamine (pKa 40) •
Soluble in organic solvents and effective at low temperature
with many compounds • Not nucleophilic
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b-Dicarbonyls Are More Acidic
• When a hydrogen atom is flanked by two carbonyl groups, its
acidity is enhanced
• Negative charge of enolate ion delocalizes over both carbonyl
groups
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Reactivity of Enolate Ions
• The carbon atom of an enolate ion is electron-rich and highly
reactive toward electrophiles (enols are not as reactive)
• Reaction on oxygen yields an enol derivative
• Reaction on carbon yields an -substituted carbonyl compound
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Alkylation of Enolate Ions
• Because the enolate has two nucleophilic sites (the oxygen and
the carbon), it can react at either of these sites.
• The reaction usually takes place primarily at the carbon, forming
a new C—C bond.
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Constraints on Enolate Alkylation
• SN2 reaction:, the leaving group X can be chloride, bromide,
iodide, or tosylate
• R should be primary or methyl and preferably should be allylic or
benzylic
• Secondary halides react poorly, and tertiary halides don't react
at all because of competing elimination
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Alkylation of Enolate Ions
• LDA forms the enolate.
• The enolate acts as the nucleophile and attacks the partially
positive carbon of the alkyl halide, displacing the halide and
forming a C—C bond.
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The Malonic Ester Synthesis
• For preparing a carboxylic acid from an alkyl halide while
lengthening the carbon chain of the substrate ( in most cases, an
alkyl halide) by two carbon atoms
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Formation of Enolate and Alkylation
• Malonic ester (diethyl propanedioate) is easily converted into
its enolate ion by reaction with sodium ethoxide in ethanol
• The enolate is a good nucleophile that reacts rapidly with an
alkyl halide to give an -substituted malonic ester
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Dialkylation
• The product has an acidic -hydrogen, allowing the alkylation
process to be repeated
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Hydrolysis and Decarboxylation
• The malonic ester derivative hydrolyzes in acid and loses CO2
(“decarboxylation”) to yield a substituted monoacid
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Decarboxylation of a b-diacid and a b- Ketoacids
• Decarboxylation requires a carbonyl group two atoms away from the
CO2H
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Overall Conversion
• The malonic ester synthesis converts an alkyl halide into a
carboxylic acid while lengthening the carbon chain by two
atoms
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• 1,4-dibromobutane reacts twice, giving a cyclic product
• Three-, four-, five-, and six-membered rings can be prepared in
this way
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Show how the malonic ester synthesis is used to prepare
2-benzylbutanoic acid.
2-Benzylbutanoic acid is a substituted acetic acid having the
substituents Ph–CH2– and CH3CH2–.
Adding these substituents to the enolate of malonic ester
eventually gives the correct
product.
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• Show how the malonic ester synthesis is used to prepare
cyclohexanecarboxylic acid.
Acetoacetic Ester Synthesis
• Overall: converts an alkyl halide into a methyl ketone
• lengthens the carbon chain of the substrate ( in most cases, an
alkyl halide) by three carbon atoms
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Acetoacetic Ester
• carbon is flanked by two carbonyl groups, so it readily becomes
an enolate ion
• This can be alkylated by an alkyl halide and also can react with
a second alkyl halide
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• Cyclic b-keto esters give 2-substituted cyclohexanones
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Decarboxylation of a b-diacid and a b- Ketoacids
• Decarboxylation requires a carbonyl group two atoms away from the
CO2H
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Show how the acetoacetic ester synthesis is used to make
3-propylhex-5-en-2-one.
The target compound is acetone with an n-propyl group and an allyl
group as substituents:
Solved Problem
Hydrolysis proceeds with decarboxylation to give the disubstituted
acetone product.
With an n-propyl halide and an allyl halide as the alkylating
agents, the acetoacetic ester synthesis
should produce 3-propyl-5-hexen-2-one. Two alkylation steps give
the required substitution:
Solved Problem (Continued) Solution (Continued)
Additional problem II
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• Show how the acetoacetic ester synthesis is used to prepare 1
-cyclopentylethanone.
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Direct Alkylation of Ketones, Esters and Nitriles
• Direct alkylation of monocarbonyl compounds can be carried out in
the presence of a strong, sterically hindered base such as LDA in a
nonprotic solvent
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Note: Alkylation prefers to occur at the less hindered, more
accessible position
Practice I:
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How would prepare each of the following compounds using direct
alkylation as the key step:
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