Chapter 4: Carboxylic acid and its

derivatives
Carboxylic Compounds
• Acyl group bonded to Y, an electronegative atom or leaving
group
• Includes: Y = halide (acid halides), acyloxy (anhydrides),
alkoxy (esters), amine (amides), thiolate (thioesters),
phosphate (acyl phosphates)

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The Importance of Carboxylic
Acids (RCO2H)
 Starting materials for acyl derivatives (esters, amides, and
acid chlorides)
 Abundant in nature from oxidation of aldehydes and
alcohols in metabolism
 Acetic acid, CH3CO2H, - vinegar

 Butanoic acid, CH3CH2CH2CO2H (rancid butter)

 Long-chain aliphatic acids from the breakdown of fats

٢
20.1 Naming Carboxylic Acids

 Carboxylic Acids, RCO2H

 If derived from open-chain alkanes, replace the
terminal -e of the alkane name with -oic acid
 The carboxyl carbon atom is C1

٤
Alternative Names

 Compounds with CO2H bonded to a ring are named

using the suffix -carboxylic acid
 The CO2H carbon is not itself numbered in this system
 Use common names for formic acid (HCOOH) and
acetic acid (CH3COOH) – see Table 20.1

٥
Nitriles,
RCN
 Closely related to carboxylic acids named by adding -
nitrile as a suffix to the alkane name, with the nitrile
carbon numbered C1
 Complex nitriles are named as derivatives of carboxylic
acids.
 Replace -ic acid or -oic acid ending with -onitrile

٦
20.2 Structure and Properties of
Carboxylic Acids
 Carboxyl carbon sp2 hybridized: carboxylic acid
groups are planar with C–C=O and O=C–O bond angles of
approximately 120°
 Carboxylic acids form hydrogen bonds, existing as cyclic
dimers held together by two hydrogen bonds
 Strong hydrogen bonding causes much higher boiling
points than the corresponding alcohols

٧
Dissociation of Carboxylic Acids
 Carboxylic acids are proton donors toward weak and
strong bases, producing metal carboxylate salts,
RCO 2  +M
 Carboxylic acids with more than six carbons are only
slightly soluble in water, but their conjugate base salts are
water-soluble

٨
Acidity Constant and p a
 Carboxylic acids transfer a proton to water to give
H3O+ and carboxylate anions, RCO , but 2 H O is
+
3 a
much stronger acid
 The acidity constant, Ka,, is about 10-5 for a typical
carboxylic acid (pKa ~ 5)

٩
 Substituent Effects on Acidity
 Electronegative substituents promote formation of the
carboxylate ion

١٠
Inductive Effects on Acidity
 Fluoroacetic, chloroacetic, bromoacetic, and iodoacetic
acids are stronger acids than acetic acid
 Multiple electronegative substituents have synergistic
effects on acidity

١
20.3 Biological Acids and the
Henderson-Hasselbalch Equation
 If pKa of given acid and the pH of the medium are
known, % of dissociated and undissociated forms
can be calculated using the Henderson-Hasselbalch
eqn

١٢
20.4 Substituent Effects on
Acidit
y

١٣
Aromatic Substituent Effects
 An electron-withdrawing group (-NO2) increases acidity
by stabilizing the carboxylate anion, and an electron-
donating (activating) group (OCH3) decreases acidity by
destabilizing the carboxylate anion
 We can use relative pKa’s as a calibration for effects on
relative free energies of reactions with the same
substituents

١٤
20.5 Preparation of Carboxylic
Acids
 Oxidation of a substituted alkylbenzene with KMnO4 or
Na2Cr2O7 gives a substituted benzoic acid (see Section
16.9)
 1° and 2° alkyl groups can be oxidized, but tertiary
groups are not

١٥
From Alkenes
 Oxidative cleavage of an alkene with KMnO4 gives a
carboxylic acid if the alkene has at least one vinylic
hydrogen (see Section 7.9)

١٦
From
Alcohols
 Oxidation of a primary alcohol or an aldehyde with
CrO3 in aqueous acid

١٧
Hydrolysis of
Nitriles
 Hot acid or base yields carboxylic acids
 Conversion of an alkyl halide to a nitrile (with cyanide ion)
followed by hydrolysis produces a carboxylic acid with one
more carbon (RBr  RCN  RCO2H)
 Best with primary halides because elimination reactions
occur with secondary or tertiary alkyl halides

١٨
Carboxylation of Grignard
Reagents
 Grignard reagents react with dry CO2 to yield a metal carboxylate
 Limited to alkyl halides that can form Grignard reagents
 The organomagnesium halide adds to C=O of carbon dioxide
 Protonation by addition of aqueous HCl in a separate step gives the
free carboxylic acid

١٩
20.6 Reactions of Carboxylic Acids:
An Overview
 Carboxylic acids transfer a proton to a base to give anions,
which are good nucleophiles in SN2 reactions
 Like ketones, carboxylic acids undergo addition of
nucleophiles to the carbonyl group
 In addition, carboxylic acids undergo other reactions
characteristic of neither alcohols nor ketones

٢٠
Naming Carboxylic Acid
Derivatives
• Acid Halides, RCOX
• Derived from the carboxylic acid name by replacing the -ic
acid ending with -yl or the -carboxylic acid ending with –
carbonyl and specifying the halide

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Naming Acid Anhydrides,
RCO2COR'
• If symnmetrical replace “acid” with “anhydride” based on
the related carboxylic acid (for symmetrical anhydrides)
• From substituted monocarboxylic acids: use bis- ahead of
the acid name
• Unsymmetrical anhydrides— cite the two acids
alphabetically

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Naming Amides, RCONH2
• With unsubstituted NH2 group. replace -oic acid or -ic
acid with -amide, or by replacing the -carboxylic acid
ending with –carboxamide
• If the N is further substituted, identify the substituent
groups (preceded by “N”) and then the parent amide

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Naming Esters, RCO2R
• Name R’ and then, after a space, the carboxylic acid
(RCOOH), with the “-ic acid” ending replaced by “-ate”

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Nucleophilic Acyl Substitution
• Carboxylic acid derivatives
have an acyl carbon bonded
to a group Y that can
leave
• A tetrahedral intermediate
is formed and the leaving
group is expelled to
generate a new carbonyl
compound, leading to
substitution

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Relative Reactivity of
Carboxylic Acid Derivatives
• Nucleophiles react more
readily with unhindered
carbonyl groups
• More electrophilic
carbonyl groups are more
reactive to addition (acyl
halides are most reactive,
amides are least)
• The intermediate with the
best leaving group
decomposes fastest

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Nucleophilic Acyl Substitution
Reactions of Carboxylic Acids
• Must enhance reactivity
• Convert OH into a better leaving group
• Specific reagents can produce acid chlorides, anhydrides,
esters, amides

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Conversion of Carboxylic Acids
into Acid Chlorides
• Reaction with thionyl chloride, SOCl2

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Conversion of Carboxylic Acids
into Acid Anhydrides
• Heat cyclic dicarboxylic acids that can form five- or six-
membered rings
• Acyclic anhydrides are not generally formed this way - they
are usually made from acid chlorides and carboxylic acids

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Conversion of Carboxylic Acids
into Esters
• Methods include reaction of a carboxylate anion with a
primary alkyl halide

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Fischer Esterification
• Heating a carboxylic acid in an alcohol solvent containing a
small amount of strong acid produces an ester from the
alcohol and acid

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Fischer Esterification: Detailed
Mechanism

1
3

2 4

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Chemistry of Acid Halides
• Acid chlorides are prepared from carboxylic acids by
reaction with SOCl2
• Reaction of a carboxylic acid with PBr3 yields the acid
bromide

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Aminolysis: Conversion of Acid
Halides into Amides
• Amides result from the reaction of acid chlorides with NH3,
primary (RNH2) and secondary amines (R2NH)
• The reaction with tertiary amines (R3N) gives an unstable
species that cannot be isolated
• HCl is neutralized by the amine or an added base

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Chemistry of Acid Anhydrides
• Prepared by nucleophilic of a carboxylate with an
acid chloride

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Acetylation
• Acetic anhydride forms acetate esters from
alcohols and N-substituted acetamides from
amines

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Chemistry of Esters
• Many esters are pleasant-smelling liquids: fragrant odors of
fruits and flowers
• Also present in fats and vegetable oils

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Preparation of Esters
• Esters are usually prepared from carboxylic acids

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Hydrolysis: Conversion of
Esters into Carboxylic Acids
• An ester is hydrolyzed by aqueous base or aqueous acid to
yield a carboxylic acid plus an alcohol

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Acid Catalyzed Ester
Hydrolysis
• The usual pathway is the reverse of the Fischer
esterification

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Reduction: Conversion of Esters
into Alcohols
• Reaction with LiAlH4 yields primary alcohols

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Chemistry of Amides
• Prepared by reaction of an acid chloride with ammonia,
monosubstituted amines, or disubstituted amines

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Uses of Reduction of Amides
• Works with cyclic and acyclic
• Good route to cyclic amines

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Polyamides and Polyesters: Step-Growth
Polymers
• Reactions occur in distinct linear steps, not as chain
reactions
• Reaction of a diamine and a diacid chloride gives an
ongoing cycle that produces a polyamide
• A diol with a diacid leads to a polyester

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