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 (k1 >> 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 >> k1):

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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 carbons
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 35

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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
Addition facilitated facilitated by
by protonation 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 anion
Ammonia is an is a very poor
excellent leaving leaving group
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 85

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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 86
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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 87
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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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