Download 18_Lecture - Ventura College

Organic Chemistry
6th Edition
Paula Yurkanis Bruice
Chapter 18
Carbonyl Compounds II
Reactions of Aldehydes and
Ketones
More Reactions of Carboxylic
Acid Derivatives
Reactions of a,b-Unsaturated
Carbonyl Compounds
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Nomenclature of Aldehydes
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If the aldehyde group is attached to a ring,
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If a compound has two functional groups, the one with the
lower priority is indicated by its prefix:
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Nomenclature of Ketones
The carbonyl is assumed to be at the 1-position in cyclic
ketones:
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If a ketone has a second functional group of higher
priority…
A few ketones have common names:
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The partial positive charge on the carbonyl carbon causes
that carbon to be attacked by nucleophiles:
An aldehyde has a greater partial positive charge on its
carbonyl carbon than does a ketone:
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Aldehydes Are More Reactive
Than Ketones
• Steric factors contribute to the reactivity of an aldehyde.
• The carbonyl carbon of an aldehyde is more accessible
to the nucleophile.
• Ketones have greater steric crowding in their transition
states, so they have less stable transition states.
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The reactivity of carbonyl compounds is also related to
the basicity of Y–:
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Carboxylic acid derivatives undergo nucleophilic acyl
substitution reactions with nucleophiles:
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Aldehydes and ketones undergo nucleophilic addition
reactions with nucleophiles:
This is an irreversible nucleophilic addition reaction if
the nucleophile is a strong base
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A reversible nucleophilic addition reaction:
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Formation of a New Carbon–Carbon
Bond Using Grignard Reagents
Grignard reagents react with aldehydes, ketones, and
carboxylic acid derivatives
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Grignard reagents are used to prepare alcohols:
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Mechanism for the reaction of an ester with a Grignard
reagent:
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Examples of Grignard
Reactions
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Reaction of Acetylide Ions with
Carbonyl Compounds
Na+ + NH3
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Reactions of Carbonyl Compounds
with Hydride Ion
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Mechanism for the reaction of an acyl chloride with
hydride ion:
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Mechanism for the reaction of an ester with hydride ion:
Esters and acyl chlorides undergo two successive
reactions with hydride ion and Grignard reagents
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Utilization of DIBALH to Control the
Reduction Reaction
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The reduction of a carboxylic acid with LiAlH4 forms a
single primary alcohol:
Acyl chloride is also reduced by LiAlH4 to yield an alcohol
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An amide is reduced by LiAlH4 to an amine
Mechanism for the reaction of an N-substituted amide
with hydride ion:
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Hydride Reducing Agents
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Selectivity of Reductions
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Hydrogen cyanide adds to aldehydes and ketones
to form cyanohydrins:
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Compared with Grignard reagents and hydride ion, CN– is
a relatively weak base; therefore, in basic solution…
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Aldehydes and ketones react with a primary amine to
form an imine:
This is a pH-dependent nucleophilic addition–
elimination reaction
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Dependence of the rate of the reaction of acetone with
hydroxylamine on the pH of the reaction: a pH-rate profile
Composition of the ratedetermining step:
Maximum rate is at
pH = pKa of +NH3OH;
at this pH, both [H+]
and [NH2OH] have the
highest values
Decreasing rate:
[H+] is decreasing
Decreasing rate:
[NH2OH] is
decreasing
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Aldehydes and ketones react with secondary amines to
form enamines:
An enamine undergoes an acid-catalyzed hydrolysis to
form a carbonyl compound and a secondary amine 31
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Enamine Reactions
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Formation of Imine Derivatives
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Types of Amine–Carbonyl
Addition Products
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Reductive Amination
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Deoxygenation of the Carbonyl Group
Called the Wolff–Kishner reduction
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Water adds to an aldehyde or ketone to form a hydrate:
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Mechanism for acid-catalyzed hydrate formation:
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Why is there such a difference in the Keq values?
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The equilibrium constant for the reaction depends on the
relative stabilities of the reactants and products:
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Addition of an Alcohol to
an Aldehyde or a Ketone
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Mechanism for acid-catalyzed acetal or ketal formation:
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Utilization of Protecting Groups
in Synthesis
LiAlH4 will reduce the ester to yield an alcohol, but
the keto group will also be reduced
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The keto group is protected as a ketal in this synthesis:
The more reactive aldehyde is protected with the diol
before reaction with the Grignard reagent:
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An OH group can be protected as a trimethylsilyl (TMS)
ether:
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Protection of an OH group in a carboxylic acid as the
ester:
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Protection of an amino group as the amide:
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Addition of Sulfur Nucleophiles
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Desulfurization replaces the C—S bonds with C—H
bonds:
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The synthetically useful aldehyde anion does
not exist
But its equivalent is accessible via the thioacetal:
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Formation of Alkenes:
The Wittig Reaction
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Preparation of the Phosphonium Ylide
The phosphonium ylide should be prepared from
sterically hindered alkyl halide:
Synthetic target:
Preferred synthetic approach:
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• The Wittig reaction is completely regioselective.
• This reaction is the best way to make a terminal alkene.
• Stable ylides form primarily E isomers, and unstabilized
ylides form primarily Z isomers.
• Stable ylides have a group (C=O) that can share the
carbanion’s negative charge.
Example:
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Stereochemistry of
Nucleophilic Addition Reaction
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Disconnections, Synthons, and
Synthetic Equivalents
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A synthetic equivalent is the reagent that is actually used
as the source of a synthon
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Nucleophilic Addition to a,bUnsaturated Aldehydes and Ketones
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• Nucleophiles that form unstable addition products form
conjugated addition products, because the conjugate
addition is not reversible.
• Nucleophiles that form stable addition products can
form direct addition products or conjugate addition
products.
• If the rate of direct addition is slowed down by steric
hindrance, a Grignard reagent will form the conjugate
addition product.
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Strong bases form direct addition products with reactive
carbonyl groups and conjugate addition products with
less reactive carbonyl groups:
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Weak bases form conjugate addition products:
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Nucleophilic Addition to a,b-Unsaturated
Carboxylic Acid Derivatives
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Enzyme-Catalyzed Additions to a,bUnsaturated Carbonyl Compounds
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Addition Reactions to a,b-Unsaturated
Carbonyls
Michael addition
nucleophiles:
• Cyanide
• Sulfide
• Organocuprate
• Amine
• Halides
Direct addition
nucleophiles:
• Grignard
• LAH
• Organolithiums
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Metabolism of acetaminophen involves conjugate
addition:
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