A library of the enol and enolate mediated carbonyl compound reactions:

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A library of the enol and enolate mediated
carbonyl compound reactions
Intermolecular a-alkylation and acetoacetic and
malonic ester synthesis via enolate
anions Chapters 22 and 23
Intramolecular a-alkylation Favorskii
rearrangement via enolate anions extra
Intermolecular a-halogenation and haloform
reaction via enols and enolate anions Chapters 22
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A library of the enol and enolate mediated
carbonyl compound reactions
Self-condensation Self and mixed Aldol and
Claisen via enols and enolate anions Chapter 23
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A library of the enol and enolate mediated
carbonyl compound reactions
Intramolecular condensation Dieckmann via enolate
anions Chapter 23
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The a Position

• The carbon next to the carbonyl group is
  designated as being in the a position
• Electrophilic substitution occurs at this
  position through either an enol or enolate ion

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Enols and enolate anions behave as nucleophiles
and react with electrophiles because the double
bonds are electron-rich compared to alkenes
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Part A KetoEnol Tautomerism

• A carbonyl compound with a hydrogen atom on its a
  carbon rapidly equilibrates with its
  corresponding enol
• Compounds that differ only by the position of a
  moveable proton are called tautomers
• The enol tautomer is usually present to a very
  small extent and cannot be isolated, but is
  formed rapidly, and serves as a reaction
  intermediate

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1H-NMR spectrum of neat 2,4-pentanedione
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Acid Catalysis of Enolization

• Brønsted acids catalyze keto-enol tautomerization
  by protonating the carbonyl and activating the a
  protons

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Base Catalysis of Enolization

• Brønsted bases catalyze keto-enol tautomerization
• The hydrogens on the a carbon are weakly acidic
  and transfer to water is slow
• In the reverse direction there is also a barrier
  to the addition of the proton from water to
  enolate carbon

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General Mechanism of Addition to Enols

• When an enol reacts with an electrophile the
  intermediate cation immediately loses the -OH
  proton to give an a-substituted carbonyl compound.

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a-Halogenation of Aldehydes and Ketones

• Aldehydes and ketones can be halogenated at their
  a positions by reaction with Cl2, Br2, or I2 in
  either the acidic or basic solutions.

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Mechanism of Acid-Catalyzed Electrophilic
Substitution
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Mechanism of Acid-Catalyzed Electrophilic
Substitution
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a-Bromoketones Undergo Facile Elimination
Reaction to Yield a,b-unsaturated Carbonyl
Compounds for 1,4-addition Reactions.
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a-Bromination of Carboxylic AcidsThe
HellVolhardZelinskii Reaction

• Carboxylic acids do not react with Br2.
• Unlike aldehydes and ketones, they are brominated
  by a mixture of Br2 and PBr3

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Mechanism of the HellVolhardZelinskii Reaction

• PBr3 converts -CO2H to COBr, which can enolize
  and add Br2

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Part B 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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Two Reactions Sites on Enolates

• Reaction on oxygen yields an enol derivative
• Reaction on carbon yields an a-substituted
  carbonyl compound

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Reagents for Enolate Formation

• Ketones are weaker acids than the OH of alcohols
  but can be deprotonated to a small extent by an
  alkoxide anion (RO-) to form the enolate. This is
  sufficient in reactions with strong electrophiles
  such as Br2.
• Sodium hydride (NaH) or lithium diisopropylamide
  LiN(i-C3H7)2 are strong enough to form large
  amounts of the enolates required for a-alkylation
  reactions.
• LDA is generated from butyllithium (BuLi) and
  diisopropylamine (pKa 40) and is soluble in
  organic solvents.

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Mechanism of Base-Promoted Electrophilic
Halogenation

• 1. The base abstracts the a-H from the keto
  tautomer.
• 2. The resulting enolate anion reacts with an
  electrophile.

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The Haloform Reaction

• Base-promoted reaction occurs through an enolate
  anion intermediate.
• Monohalogenated products are themselves rapidly
  turned into enolate anions and further
  halogenated until the trihalo compound is formed
  from a methyl ketone.
• The product is cleaved by hydroxide with -CX3 as
  a leaving group.

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a-Alkylation of Enolate Ions via Lithium Enolate
Salts

• Even unreactive ketones will be easily
  deprotonated with LDA to give stable, isolable
  lithium enolate salts.

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a-Alkylation of Enolate Ions

• Alkylation occurs when the nucleophilic enolate
  ion reacts with the electrophilic alkyl halide or
  tosylate and displaces the leaving group

• 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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Mechanism of Base-Promoted Electrophilic
Alkylation
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Intramolecular a-alkylation reaction Favorskii
rearrangement.
Intramolecular a-alkylation in the Favorskii
rearrangement proceeds via enolate anion
generated within the molecule. The molecule must
contain a leaving group, usually a halide. The
purpose of the reaction is two fold 1. Molecular
rearrangements of ketones to carboxylic acids and
2. Ring contraction reaction to make high energy
small size and/or fused rings.
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Mechanism
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Intramolecular a-alkylation reaction Favorskii
rearrangement resulting in ring contractions.
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ß-Dicarbonyls Are More Acidic

• When a hydrogen atom is flanked by two carbonyl
  groups, its acidity is enhanced (Table 22.1)
• Negative charge of enolate delocalizes over both
  carbonyl groups

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Relative acidities are dictated by the
substituents on the carbonyl group.
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Ethyl Acetoacetate Ester
Diethyl Malonate Ester
Acetoacetic and malonic esters are easily
converted into the corresponding enolate anions
by reaction with sodium ethoxide in ethanol. The
enolates are good nucleophiles that react rapidly
with alkyl halides to give an a-substituted
derivatives. The product has an acidic
a-hydrogen, allowing the alkylation process to be
repeated.
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Formation of Enolate and Alkylation
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Formation of Enolate and Alkylation
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2. The Malonic Ester Synthesis

• For preparing a carboxylic acid from an alkyl
  halide while lengthening the carbon chain by two
  atoms

3. The Acetoacetic Ester Synthesis

• Overall converts an alkyl halide into a methyl
  ketone

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Synthesis of ketones using acetoacetic ester via
the decarboxylation of acetoacetic acid

• b-Ketoacid from hydrolysis of ester undergoes
  decarboxylation to yield a ketone via the enol

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Synthesis of carboxylic acids using malonic ester
via the decarboxylation of malonic acid

• The malonic ester synthesis converts an alkyl
  halide into a carboxylic acid while lengthening
  the carbon chain by two atoms

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Decarboxylation of b-Ketoacids

• Decarboxylation requires a carbonyl group two
  atoms away from the ß CO2H
• The second carbonyl permit delocalization of the
  resulting enol
• The reaction can be rationalized by an internal
  acid-base reaction

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Generalization b-Keto Esters

• The sequence enolate ion formation, alkylation,
  hydrolysis/decarboxylation is applicable to
  b-keto esters in general
• Cyclic b-keto esters give 2-substituted
  cyclohexanones

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Preparation Cycloalkane Carboxylic Acids

• 1,4-dibromobutane reacts twice, giving a cyclic
  product
• Three-, four-, five-, and six-membered rings can
  be prepared in this way