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Organic Chemistry
6th Edition
Paula Yurkanis Bruice
Chapter 17
Carbonyl
Compounds I
Reactions of
Carboxylic Acids and
Carboxylic Acid
Derivatives
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Class I Carbonyl Compounds
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Class II Carbonyl Compounds
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Nomenclature of Carboxylic Acids
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In systematic nomenclature, the carbonyl carbon is
always C-1
In common nomenclature, the carbon next to the
carbonyl is the a-carbon
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The functional group of a carboxylic acid is called a
carboxyl group
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Naming Cyclic Carboxylic Acid
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Salts of Carboxylic Acids
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Acyl Halides
Acid Anhydrides
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Esters
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Cyclic esters are known as lactones:
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Amides
If a substituent is bonded to the nitrogen, the name of the
substituent is stated first:
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Cyclic amides are known as lactams:
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Nitriles
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Structures of Carboxylic Acids and
Carboxylic Acid Derivatives
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Two major resonance contributors in esters,
carboxylic acids, and amides:
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Carboxylic acids have relatively high boiling points
because…
Amides have the highest boiling points:
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Naturally Occurring Carboxylic Acids and
Carboxylic Acid Derivatives
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The reactivity of carbonyl compounds resides in the
polarity of the carbonyl group:
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The tetrahedral intermediate is a transient species that
eliminates the leaving group Y– or the nucleophile Z–:
This is a nucleophilic acyl substitution reaction
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Z– will be expelled if it is a much weaker base than Y–;
that is, Z– is a better leaving group than Y– (k–1 >> k2):
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Y– will be expelled if it is a weaker base than Z–; that is,
Y– is a better leaving group than Z– (k2 >> k–1):
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Both reactant and product will be present if Y– and Z–
have similar leaving abilities:
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Reaction Coordinate Diagrams for
Nucleophilic Acyl Substitution Reactions
(a) the Nu– is a weaker base
(b) the Nu– is a stronger base
(c) the Nu– and the leaving group have similar basicities
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A Molecular Orbital Description of How
Carbonyl Compounds React
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The reactivity of a carboxylic acid derivative depends on
the basicity of the substituent attached to the acyl group:
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Electron withdrawal increases the carbonyl carbon’s
susceptibility to nucleophilic attack:
The weaker the basicity of Y, the greater the reactivity:
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Weak bases are easier to expel when the tetrahedral
intermediate collapses:
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A carboxylic acid derivative can be converted only into a
less reactive carboxylic acid derivative:
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The tetrahedral intermediate eliminates the weaker base:
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If the nucleophile is neutral…
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Reactions of Acyl Halides
A base is required to
trap the HCl product
Suitable bases include triethylamine (TEA) and pyridine
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TEA
Excess amine
traps HCl
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Formation of Amides from Acyl Halides
Tertiary amines cannot form amides
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Reactions of Acid Anhydrides
Acid anhydrides do not react with sodium chloride or
with sodium bromide because Cl– and Br– are weaker
bases than acetate
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Anhydride reactions are facilitated by acid or base catalysts
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Mechanism for the conversion of an acid
anhydride into an ester (and a carboxylic acid):
Elimination
facilitated by
protonation
Addition facilitated
by protonation
In the absence of an acid catalyst, the reaction is
sluggish, but the reaction speeds up as acid
products are formed
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Reactions of Esters
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Phenyl esters are more reactive than alkyl esters because
phenolate ions are weaker bases than alkoxide ions:
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Hydrolysis of an ester with primary or secondary alkyl
groups can be catalyzed by an acid
The carbonyl oxygen is first protonated,
Because…
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There are no negatively charged species in the reaction:
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Excess water will force the equilibrium to the right
Alcohols that have low boiling points can be removed by
distillation as they are formed
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Acid catalyzes the reaction by…
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An acid catalyst can make a group a better leaving group:
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Esters with tertiary alkyl groups undergo hydrolysis much
more rapidly than do others:
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Transesterification is also catalyzed by acid:
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Hydroxide ion increases the rate of formation as well as
the collapse of the tetrahedral intermediate:
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Elucidating the reaction mechanism of nucleophilic acyl
substitution:
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Fats and Oils Are Triesters of Glycerol
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Long-chain carboxylate ions form micelles:
• The nonpolar tails are buried in the hydrophobic interior.
• The polar carboxylates are positioned at the aqueous exterior.
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Reactions of Carboxylic Acids
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Carboxylic acids do not undergo nucleophilic acyl
substitution reactions with amines at room temperature
Heating the ammonium carboxylate will afford the
amide and water
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Reactions of Amides
Amides are very unreactive carboxylative derivatives
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Amides can react with water and alcohols if an acid
catalyst is present:
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Dehydration of an Amide
Dehydration reagents commonly used are SOCl2, P2O5,
or POCl3
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An acid catalyst can make the amine a better leaving
group:
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The need for an acid catalyst…
Ammonia is an
excellent leaving
group
Ammonia anion
is a very poor
leaving group
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Hydrolysis of an Imide:
The Gabriel Synthesis
This is a way to synthesize amines
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The Hydrolysis of Nitriles
Mechanism:
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Designing the Synthesis of Cyclic
Compounds
Formation of lactones:
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Preparation of a compound with a ketone group attached
to a benzene ring:
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Preparation of a cyclic ether:
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Activation of Carboxylic Acids
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The goal is to convert the OH group into a better leaving
group:
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The acyl halide can be used to prepare other carboxylic
acid derivatives:
TEA
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Activated Carboxylic Acid Derivatives
in Living Organisms
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Attack of a nucleophile breaks a phosphoanhydride
bond:
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The carbonyl carbon of a thioester is more susceptible to
nucleophilic attack than is the carbonyl carbon of an
oxygen ester
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Dicarboxylic acids readily lose water upon heating if
they can form a five- or six-member cyclic anhydride
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The two pKa values of a dicarboxylic acid are different:
Why?
• The neighboring COOH group withdraws electrons
and lowers the first pKa.
• Electrostatic interaction between like charges raises
the second pKa.
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Preparation of Cyclic Anhydrides from
Dicarboxylic Acids
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Substitution Reactions of Acid
Chlorides
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Substitution Reactions of
Anhydrides
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Substitution Reactions of Esters
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Substitution Reactions of
Amides and Acids
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Olestra
Tastes like a fat, but the
sterically hindered
esters cannot be
digested
Shown are esters of common fatty
acids (actually, a variety of fatty
ester combinations makes up
Olestra)
Sucrose esterified with fatty acids
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Acetylcholinesterase
Terminates the cholinergic signal by
hydrolyzing acetylcholine:
Mechanism involves acetyl transfer
to a serine oxygen
Cholinergic activity
= SLUD
Salivation
Urination
Lacrimation
Defecation
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Nerve Gases
• Nerve gases phosphorylate the active-site
serine oxygen of acetylcholinesterase.
• Acetylcholine builds up, resulting in
“SLUD” and eventually death by
convulsions.
• Nerve gases are actually high-boiling
liquids that are used as aerosols.
The phosphorylation reaction requires the
presence of a good leaving group
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Bioactivation of Acetate
The –SCoA leaving group is highly functionalized so
that acetyl transfer does not occur randomly
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Biosynthesis of Acetylcholine
The choline from the acetylcholinesterase-mediated hydrolysis of
acetylcholine is taken up by the presynaptic cholinergic neuron and
reacetylated:
The acetylcholine is stored for the next nerve impulse
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Penicillin
The strained lactam ring acylates a serine
hydroxyl of a transpeptidase,
resulting in the absence of peptidoglycan cross-links
required for the bacterial cell wall synthesis
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Bacteria can become resistant to penicillin by
producing an enzyme that hydrolyzes the lactam ring:
Changing the R group can overcome resistance as well as
increase the spectrum of activity:
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