Organic Chemistry II / CHEM

252
Chapter 18 – Carboxylic Acids and
Their Derivatives.
Bela Torok
Department of Chemistry
University of Massachusetts Boston
Boston, MA
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 Introduction

• The carboxyl group (-CO2H) is the parent group of a family of

compounds called acyl compounds or carboxylic acid derivatives

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Nomenclature and Physical Properties
• In IUPAC nomenclature, the name of a carboxylic acid is obtained by
changing the -e of the corresponding parent alkane to -oic acid
– The carboxyl carbon is assigned position 1 and need not be
explicitly numbered

• The common names for many carboxylic acids remain in use

– Methanoic and ethanoic acid are usually referred to as formic and
acetic acid
• Carboxylic acids can form strong hydrogen bonds with each other and
with water
– Carboxylic acids with up to 4 carbons are miscible with water in
all proportions
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Nomenclature and Physical Properties

4
 Acidity
• The carboxyl proton of most carboxylic acids has a pKa = 4 - 5
– Carboxylic acids are deprotonated by NaOH or NaHCO3
– Carboxylate salts are more water soluble than the acid

• Electron-withdrawing groups increase the acidity

– They stabilize the carboxylate anion by inductive delocalization of
charge

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 Dicarboxylic Acids
• Dicarboxylic acids are named as alkanedioic acids in the IUPAC
system
– Common names are often used for simple dicarboxylic acids

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 Esters
• The names of esters are derived from the names of the corresponding
carboxylic acid and alcohol from which the ester would be made
– The alcohol portion is named first and has the ending -yl
– The carboxylic acid portion follows and its name ends with -ate or -
oate

• Esters cannot hydrogen bond to each other and therefore have lower
boiling points than carboxylic acids
– Esters can hydrogen bond to water and have appreciable water
solubility
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Esters

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 Acid Anhydrides, Chlorides
– Acid Anhydrides
• Most anhydrides are named by dropping the word acid from the
carboxylic acid name and adding the word anhydride

– Acid Chlorides
• Acid chlorides are named by dropping the -ic acid from the name of the
carboxylic acid and adding -yl chloride

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 Amides
• Amides with no substituents on nitrogen are named by replacing
-ic acid in the name with amide
– Groups on the nitrogen are named as substitutents and are given the
locants N- or N,N-

• Amides with one or two hydrogens on nitrogen form very strong

hydrogen bonds and have high melting and boiling points
– N,N-disubstituted amides cannot form hydrogen bonds to each other
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and have lower melting and boiling points
 Amides, Nitriles
• Hydrogen bonding between amides in proteins and peptides is an
important factor in determining their 3-dimensional shape

– Nitriles
• Acyclic nitriles are named by adding the suffix -nitrile to the
alkane name
– The nitrile carbon is assigned position 1
– Ethanenitrile is usually called acetonitrile

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 Preparation of Carboxylic Acids
– By Oxidation of Alkenes

– By Oxidation of Aldehydes and Primary Alcohols

– By Oxidation of Alkylbenzenes

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 Preparation of Carboxylic Acids
– By Oxidation of the Benzene Ring

– By Oxidation of Methyl Ketones (The Haloform Reaction)

– By Hydrolysis of Cyanohydrins and Other Nitriles

– Hydrolysis of a cyanohydrin yields an α-hydroxy acid

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 Preparation of Carboxylic Acids
– Primary alkyl halides can react with cyanide to form
nitriles and these can be hydrolyzed to carboxylic acids

– By Carbonation of Grignard Reagents

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 Nucleophilic Addition-Elimination
• Recall that aldehydes and ketones undergo nucleophilic addition to the
carbon-oxygen double bond

• The carbonyl group of carboxylic acids and their derivatives undergo

nucleophilic addition-elimination
– The nucleophile reacts at the carbonyl group
– The tetrahedral intermediate eliminates a leaving group (L)
– The carbonyl group is regenerated; the net effect: acyl substitution

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 Nucleophilic Addition-Elimination
• To undergo nucleophilic addition-elimination the acyl
compound must have a good leaving group or a group that can
be converted into a good leaving group
– Acid chlorides react with loss of chloride ion
– Anhydrides react with loss of a carboxylate ion

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 Nucleophilic Addition-Elimination
• Esters, carboxylic acids and amides generally react with loss of
the leaving groups alcohol, water and amine, respectively
– These leaving groups are generated by protonation of the
acyl compound
• Aldehydes and ketones cannot react by this mechanism
because they lack a good leaving group

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 Relative Reactivity
– Relative Reactivity of Acyl Compounds
• The relative reactivity of carboxylic acids and their derivatives is as
follows:

• Reactivity can be related to the ability of the leaving group (L) to depart
– Leaving group ability is inversely related to basicity
– Chloride is the weakest base and the best leaving group
– Amines are the strongest bases and the worst leaving groups
• Less reactive acyl compounds can be synthesized from more reactive ones
– Synthesis of more reactive acyl derivatives from less reactive ones is
difficult and requires special reagents (if at all possible)
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 Acyl Chlorides
Synthesis of Acid Chlorides
• Acid chlorides are made from carboxylic acids by reaction with
thionyl chloride, phosphorus trichloride or phosphorus pentachloride
– These reagents work because they turn the hydroxyl group of the
carboxylic acid into an excellent leaving group

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 Acyl Chlorides

– Reactions of Acyl Chlorides

• Acyl chlorides are the most reactive acyl compounds and can
be used to make any of the other derivatives
• Since acyl chlorides are easily made from carboxylic acids
they provide a way to synthesize any acyl compound from a
carboxylic acid
• Acyl chlorides react readily with water, but this is not a
synthetically useful reaction
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Acyl Chlorides

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 Carboxylic Acid Anhydrides
– Synthesis of Carboxylic Acid Anhydrides
• Acid chlorides react with carboxylic acids to form mixed or symmetrical
anhydrides
– It is necessary to use a base such as pyridine

• Sodium carboxylates react readily with acid chlorides to form

anhydrides

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 Carboxylic Acid Anhydrides
• Cyclic anhydrides with 5- and 6-membered rings can be
synthesized by heating the appropriate diacid

– Reactions of Carboxylic Acid Anhydrides

• Carboxylic acid anhydrides are very reactive and can be used
to synthesize esters and amides
– Hydrolysis of an anhydride yields the corresponding
carboxylic acids

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Carboxylic Acid Anhydrides

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 Carboxylic Acid Esters
Synthesis of Esters: Esterification
• Acid catalyzed reaction of alcohols and carboxylic acids to form esters
is called Fischer esterification
• Fischer esterification is an equilibrium process
– Ester formation is favored by use of a large excess of either the
alcohol or carboxylic acid
– Ester formation is also favored by removal of water

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 Carboxylic Acid Esters
• Esterification with labeled methanol gives a product labeled only at the
oxygen atom bonded to the methyl group
– A mechanism consistent with this observation is shown below

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 Carboxylic Acid Esters
• The reverse reaction is acid-catalyzed ester hydrolysis
– Ester hydrolysis is favored by use of dilute aqueous acid

• Esters from Acid Chlorides

– Acid chlorides react readily with alcohols in the presence of a base
(e.g. pyridine) to form esters

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 Carboxylic Acid Esters
• Esters from Carboxylic Acid Anhydrides
– Alcohols react readily with anhydrides to form esters

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 Carboxylic Acid Esters
– Base-Promoted Hydrolysis of Esters: Saponification
• Reaction of an ester with sodium hydroxide results in the formation
of a sodium carboxylate and an alcohol

• The mechanism is reversible until the alcohol product is formed

• Protonation of the alkoxide by the carboxylic acid is irreversible
– This step draws the overall equilibrium toward the hydrolysis

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 Carboxylic Acid Esters
– Lactones
γ- or δ-Hydroxyacids undergo acid catalyzed reaction to give
cyclic esters known as γ- or δ-lactones, respectively

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 Carboxylic Acid Esters
• Lactones can be hydrolyzed with aqueous base
– Acidification of the carboxylate product can lead back to the
original lactone if too much acid is added

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 Amides
Synthesis of Amides
• Amides From Acyl Chlorides
– Ammonia, primary or secondary amines react with acid
chlorides to form amides
– An excess of amine is added to neutralize the HCl formed
in the reaction
– Carboxylic acids can be converted to amides via the
corresponding acid chloride

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 Amides
• Amides from Carboxylic Anhydrides
– Anhydrides react with 2 equivalents of amine to produce an amide
and an ammonium carboxylate

– Reaction of a cyclic anhydride with an amine, followed by

acidification yields a product containing both amide and carboxylic
acid functional groups
– Heating this product results in the formation of a cyclic imide

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 Amides
• Amides from Carboxylic Acids and Ammonium Carboxylates
– Direct reaction of carboxylic acids and ammonia yields ammonium
salts

– Some ammonium salts of carboxylic acids can be dehydrated to the

amide at high temperatures
– This is generally a poor method of amide synthesis

– A good way to synthesize an amide is to convert a carboxylic acid to

an acid chloride and to then to react the acid chloride with ammonia
or an amine
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 Amides
– Dicylohexylcarbodiimide (DCC) is a reagent used to form amides
from carboxylic acids and amines
– DCC activates the carbonyl group of a carboxylic acid

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 Amides
– Hydrolysis of Amides
• Heating an amide in concentrated aqueous acid or base causes hydrolysis
– Hydrolysis of an amide is slower than hydrolysis of an ester

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Amides

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Amides

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 Amides
– Nitriles from the Dehydration of Amides
• A nitrile can be formed by reaction of an amide with phosphorous
pentoxide or boiling acetic anhydride

– Hydrolysis of Nitriles
• A nitrile is the synthetic equivalent of a carboxylic acid because it can be
converted to a carboxylic acid by hydrolysis

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Amides

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Amides

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 Decarboxylation
• Decarboxylation of Carboxylic Acids
β-Keto carboxylic acids and their salts decarboxylate readily when
heated
– Some even decarboxylate slowly at room temperature

• The mechanism of β-keto acid decarboxylation proceeds through a

6-membered ring transition state

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 Decarboxylation
• Carboxylate anions decarboxylate rapidly because they form a
resonance-stabilized enolate

• Malonic acids also decarboxylate readily

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