Carbonyl AlphaSubstitution Reactions Capter22

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Carbonyl Alpha-Substitution ReactionsCapter-22

• Chem. 233 Fall 2004
• Dr. Zand

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Sneak Peek

• Keto-Enol Tautomerism
• Reactivity of Enols Mech. of
  Alpha-Substitution Rxns.
• Alpha Halogenation of Aldehydes and Ketones
• Alpha Bromination of Carboxylic Acids
• The Hell-Volhard-Zelinskii Rxn.
• Acidity of Alpha Hydrogen Atoms Enolate Ion
  Formation
• Reactivity of Enolate Ions
• Halogenatation of Enolate Ions The Haloform
  Rxn.
• Alkylation of Enolate ions

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a-substitution Reaction
An enolate ion
An alpha-substituted carbonyl compound
A carbonyl compound
An enol
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Keto-Enol Tautomerism

• A. Natures of tautomerism.
• 1. Carbonyl compounds with hydrogens bonded to
  their a carbons equilibrate with their
  corresponding enols.
• 2. This rapid equilibration is called
  tautomerism, and the individual isomers are
  tautomers.
• 3. Unlike resonance forms, tautomers are isomers.
• 4. Despite the fact that very little of the enol
  isomer is present at room temperature, enols are
  very important because they are reactive.
• B. Mechanism of tautomerism.
• 1. In acid-catalyzed enoliztion, the carbonyl a
  carbon is protonated to form an intermediate that
  can lose a hydrogen from its carbon to yield a
  neutral enol.
• 2. In base-catalyzed enol formation, an
  acid-0base reaction occurs between a base and an
  a hydrogen.
• a. The resultant enolate is potonated to yield
  an enol.
• b. Protonation can occur either on carbon or on
  oxygen.
• c. Only hydrogen on the a positions of carbonyl
  compounds are acidic.

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Acid-catalyzed Enol Formation
HA
Acid-catalyzed enol formation. The protonated
intermediate can lose H, either from the oxygen
atom to regenerate keto tautomer or from the a
carbon atom to yield an enol.
Keto tautomer
Protonation of the carbonyl oxygen atom by an
acid catalyst HA yield a cation that can be
represented by two resonance structures.
A-
Loss of H from the a position by reaction with a
base A- then yields the enol tautomer and
regenerates HA catalyst.
HA
Enol tautomer
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Base-catalyzed Enol Formation
Base-catalyzed enol formation. The intermediate
enolate ion, a resonance hybrid of two forms, can
be protonated either on carbon to regenerate the
starting keto tautomer or on oxygen to give an
enol.
Keto tautomer
Base removes an acidic hydrogen from the a
position of the carbonyl compound, yielding an
enolate anion that has two resonance structures.
Protonation of the enolate anion on the oxygen
atom yields an enol and regenerates the base
catalyst.
OH-
Enol tautomer
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Reactivity of Enols Mech. of Alpha-Substitution
Rxns

• 1. The electron-rich double bonds of enols cause
  them to behave as nucleophiles.
  
  (The electron-donating enol -OH
  groups make enols more reactive then alkenes)
• 2. When an enol reacts with an electrophile, the
  initial adduct loses -H from oxygen to give a
  substituted carbonyl compound

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Enol tautomer
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Alpha Halogenation of Aldehydes and Ketones

• 1. Aldehydes and ketones can be halogenated at
  their a positions by reaction of X2 in acidic
  solution.
• 2. The reaction proceeds by acid-catalyzed
  formation of an enol intermediate.
• 3. Halogen isnt involved in the rate-limiting
  step the rate doesnt depend on the identity of
  the halogen, but only on ketone and H.
• 4. a-Bromo ketones are useful in synthesis
  because they can be dehydrobrominated by base
  treatment to from a,ß-unsaturated ketones.

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Carbonyl a-substitution Rxn.
Acid-catalyzed enol formation occurs by the usual
mechanism.
E
Carbonyl asubstitution Rxn. The initial formed
cation loses H to regenerate a carbonyl compound.
An electron pair from the enol oxygen attacks an
electrophile (E), forming a new bond and leaving
a cation intermediate that is stabilized by
resonance between two forms.
Loss of a proton from oxygen yields the neutral
a-substitution product as a new CO bond is
formed.
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ExamplesAldehydes and ketones can be
halogenated at their a positions by reaction with
Cl2, Br2, or I2 in acidic solution. Bromine in
acetic acid solvent is often used.
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Acid-catalyzed bromination of acetone
HBr
BrBr
Br-
Enol
The carbonyl oxygen atom is protpnated by acid
catalyst.
Loss of an acidic proton from the alpha carbon
takes place in the normal way to yield an enol
intermediate
An electron pair from the enol attacks bromine,
giving an intermediate cation that is stabilized
by resonance between two forms.
Loss of the OH proton then gives the
alpha-halongenated product and generates more
acid catalyst.
HBr
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Alpha Bromination of Carboxylic Acids The
Hell-Volhard-Zelinskii Rxn

• 1. In the Hell-Volhard-Zelinskii (HVZ) reaction,
  a mixture of Br2 and PBr3 can be used to
  brominate carboxylic acids in the a position.
• 2. The initially formed acid bromide reacts with
  Br2 to form an abromo acid bromide, which is
  hydrolyzed by water to give the abromo
  carboxylic acid.
• 3. The reaction proceeds through an acid bromide
  enol.

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The Hell-Volhard-Zelinskii Rxn
1st step takes place between PBr3 and a
carboxylic acid to yield an intermediate acid
bromide plus HBr.
The Hell-Volhard-Zelinskii Rxn. The overall
result of the reaction is the transformation of
an acid into an a-bromo acid. Note, though, that
the key step involves a substitution of an acid
bromide enol rather than a carboxylic acid enol.
Acid bromide
Acid bromide enol
The HBr catalyzes enolization of the acid bromide
and the resultant enol reacts rapidly with Br2 in
an a-substitution rxn.
Addition of H2O results in hydrolysis of the
a-bromo acid bromide and gives the a-bromo
carboxylic acid product.
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Acidity of Alpha Hydrogen Atoms Enolate Ion
Formation

• 1. Hydrogens a to a carbonyl group are weakly
  acidic.
• a. This stability is due to overlap of a vacant
  ? orbital with the carbonyl group ? orbitals,
  allowing the carbonyl group to stabilize the
  negative charge by resonance.
• b. The two resonance forms arent equivalent
  the form with the negative charge on oxygen is
  of lower energy.
• 2. Strong bases are needed for enolate ion
  formation.
• a. Alkoxide ions are too weak to use in enolate
  formation.
• b. Lithium diisopropylamide (LDA) is used for
  forming enolates because it is a very strong
  base, it is soluble in THF, it is hindered and it
  can be used at low temperatures.
• c. LDA can be used to form the enolate of many
  different carbonyl compounds.
• 3. When a hydrogen is flanked by two carbonyl
  groups, it is much more acidic.
• (Both carbonyl groups can stabilize the negative
  charge.)

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Acidity Constants for Some Organic Compounds
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Reactivity of Enolate Ions

• 1. Enolates are more useful than enols for two
  reasons
• a. Unlike enols, stable solutions of enlolates
  are easily prepared.
• b. Enolates are more reactive then enols because
  they are more neucleophilic.
• 2. Enolates can react either at carbon or at
  oxygen.
• a. Reaction at carbon yields an a-substituted
  carbonyl compound.
• b. Reaction at oxygen yields an enol derivative.

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Reactivity of Enolate Ions
Relativity of Enolate Ions. Two modes of
reaction of an enolate ion with an electrophile,
E. Reaction on carbon to yield an a-substituted
carbonyl product is more common.
?-Keto canbanion
Vinylic alkoxide
An a-substituted carbonyl compound
An enol derivative
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Halogenatation of Enolate Ions The Haloform Rxn

• 1. Base-promoted halogenation of aldehydes and
  ketones proceeds readily because each halogen
  added makes the carbonyl compound more reactive.
• 2. Consequently, polyhalogenated compounds are
  usually produced.
• 3. This reaction is only useful with methyl
  ketones, which form HCX3 when reacted with
  halogens.
• a. The HCX3 is a solid that can be identified.
• b. The last step of the reaction involves a
  carbanion leaving group.

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The Haloform Rxn
The Haloform Rxn. If excess base and halogen
are used, a methyl ketone is triply halogenate
and then cleaved by a base. The products are a
carboxylic acid plus a so-called haloform. Note,
that the 2nd step of the rxn is a nucleophillic
acyl substitution of CX3 by OH. That is, a
carbanion acts as a leaving grp.
A methyl ketone
-CX3
CHX3
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Alkylation of Enolate ions

• 1. General features.
• a. Alkylatons are useful because they form a
  new CC bond.
• b. Alkylations have the same limitations as SN2
  reactions the alkyl groups must be methyl,
  primary, allylic or benzylic.
• 2. The malonic ester synthesis.
• a. The malonic ester synthesis is used for
  preparing a carboxylic acid from a halide while
  lengthening the chain by two atoms.
• b. Diethyl malonate is useful because its
  enolate is easily prepared by reaction with
  sodium ethoxide.
• c. Since diethyl malonate has two acidic
  hydrogens, two alkylations can take place.
• d. Heating in aqueous HCL causes hydrolysis and
  decarboxylation of the alkylated malonate.
• (Decarboxylations are common only to ßketo
  acids and malonic acids.)
• e. Cycloalkanecarboxylic acids can also be
  prepared.

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The Malonic Ester Synthesis
Sodio malonic ester
Diethyl propanedioate (malonic ester)
An alkylated malonic ester
CO2 2 EtOH
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Alkylation of Enolate ions cont...

• 3. The acetoacetic ester synthesis.
• a. The acetoacetic ester synthesis is used for
  converting an alkyl halide to a methyl ketone,
  while lengthening the the carbon chain by 3
  atoms.
• b. As with malonic ester, acetoacetic ester has
  two acidic hydrogens which are flanked by a
  ketone and an ester, and two alkylations can take
  place.
• c. Heating in aqueous HCL hydrolyzes the ester
  and decarboxylate the acid to yield the ketone.
• d. All ßketo esters can undergo this type of
  reaction.
• 4. Direct alkylation of ketones, esters, and
  nitriles.
• a. LDA in a nonprotic solvent can be used to
  convert the above compounds to their enolates.
• b. Alkylation of an unsymmetrical ketone leads
  to a mixture of products, but the major product
  is alkylated at the less hindered position.

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The Acetoacetic Ester Synthesis
Acetoacetic ester
A monoalkylated acetoacetic ester
A monoalkylated acetoacetic ester
A dialkylatedn acetoacetic ester
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Alkylation of ketones
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Alkylation of esters
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Alkylation of nitriles