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Organic Chemistry, 6th ed.

Marc Loudon and Jim Parise

Chapter 21
The Chemistry of Carboxylic Acid Derivatives
Chapter 21 Overview
21.1 – Nomenclature and Classification of Carboxylic Acid
Derivatives
21.2 – Structures of Carboxylic Acid Derivatives
21.3 – Physical Properties of Carboxylic Acid Derivatives
21.4 – Spectroscopy of Carboxylic Acid Derivatives
21.5 – Basicity of Carboxylic Acid Derivatives
21.6 – Introduction to Reactions of Carboxylic Acid Derivatives
21.7 – Hydrolysis of Carboxylic Acid Derivatives
21.8 – Reactions of Carboxylic Acid Derivatives with Nucleophiles
21.9 – Reduction of Carboxylic Acid Derivatives
21.10 – Reactions of Carboxylic Acid Derivatives with
Organometallic Reagents
21.11 – Synthesis of Carboxylic Acid Derivatives
21.12 – Use and Occurrence of Carboxylic Acids and Their
Derivatives.
2
Carboxylic Acid Derivatives
• A carboxylic acid derivative is a compound that can
be hydrolyzed under acidic or basic conditions to give
the related carboxylic acid.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 3


Esters
• Named as a derivative of their parent carboxylic
acids by applying a variation of the system used to
name carboxylate salts.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 4


Esters

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 5


Lactones
• Cyclic esters are called lactones.
• The name is derived from the acid with the same
number of carbons in the principle chain.
• The ring size is denoted by a Greek letter
indicating the point of attachment.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 6


Acid Halides
• Replace the ic ending with yl followed by the
name of the halide.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 7


Anhydrides
• Name the parent acid is followed by anhydride.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 8


Nitriles
• Drop the ic or oic ending and add onitrile.
• The nitrile carbon counts as part of the chain
length.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 9


Amides
• Replace the ic or oic and add amide.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 10


Amides
• Amides are classified according to the number of
hydrogens on the amide nitrogen.

• Use N for substituents on the nitrogen.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 11


Lactams
• Cyclic amides are called lactams.
• The nomenclature follows that of lactones.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 12


Imides
• Imides are the nitrogen analogs of anhydrides.
• Cyclic imides are of greater importance than open-
chain imides.

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 13


Nomenclature of Substituent Groups
• The priorities for citing principle groups in a
carboxylic acid derivative are:

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 14


Nomenclature of Substituent Groups

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 15


Carbonic Acid Derivatives
• Esters of carbonic acid are named like any other
ester.

• Other important derivatives include:

21.1 Nomenclature and Classification of Carboxylic Acid Derivatives 16


Structures of Carboxylic Acid Derivatives
• The derivatives are very similar to other carbonyl
compounds (bond lengths, angles).
• In an amide, both the carbonyl carbon and the
amide nitrogen have trigonal planar bonding.

21.2 Structures of Carboxylic Acid Derivatives 17


Structures of Carboxylic Acid Derivatives
• Because of the trigonal planar geometry at
nitrogen, E and Z conformers are possible.

• The interconversion is relatively rapid at room


temperature (~10 s-1, E barrier  71 kJ mol-1).

21.2 Structures of Carboxylic Acid Derivatives 18


Physical Properties of Esters
• Polar; H-bond acceptors only.
• Typically volatile, fragrant liquids.
• Most are insoluble in water.

21.3 Physical Properties of Carboxylic Acid Derivatives 19


Physical Properties of Anhydrides and Acid Chlorides
• Lower anhydrides and acid chlorides are dense,
water-insoluble liquids.
• They typically have acrid, piercing odors.

21.3 Physical Properties of Carboxylic Acid Derivatives 20


Physical Properties of Nitriles
• Highly polar (3.4 D for H3C-CN) which is reflected
in the high boiling point of nitriles.

• Nitriles larger than propionitrile are water-


insoluble.
• Acetonitrile is a useful polar, aprotic solvent.

21.3 Physical Properties of Carboxylic Acid Derivatives 21


Physical Properties of Amides
• Polar with high boiling points.
• Lower amides are water-soluble.
• Tend to aggregate due to H-bonding.

21.3 Physical Properties of Carboxylic Acid Derivatives 22


IR Spectroscopy

21.4 Spectroscopy of Carboxylic Acid Derivatives 23


IR Spectroscopy: Esters
• C=O stretch: 1735-1745cm-1.
• Readily distinguishes them from carboxylic acids,
aldehydes, and ketones.

21.4 Spectroscopy of Carboxylic Acid Derivatives 24


IR Spectroscopy: Anhydrides
• Two C=O stretches (also common for some acid
chlorides).
• Due to symmetric and asymmetric stretching.

21.4 Spectroscopy of Carboxylic Acid Derivatives 25


IR Spectroscopy: Amides
• C=O stretch: 1650-1675 cm-1.
• Much lower than other C=O stretches.

21.4 Spectroscopy of Carboxylic Acid Derivatives 26


IR Spectroscopy: Amides
• Primary, secondary,
and tertiary amides
can also be
differentiated.

21.4 Spectroscopy of Carboxylic Acid Derivatives 27


IR Spectroscopy: Nitriles
• CN stretch: 2200-2250 cm-1.
• Normally much stronger than CC stretch due to
the large bond dipole.

21.4 Spectroscopy of Carboxylic Acid Derivatives 28


1H NMR Spectroscopy
• a-Hydrogens next to carbonyl: d 1.9-3 region.
• Hydrogens on carbon next to alkoxy O: +0.6 ppm more
than for that of alcohols and ethers.
• Amide NH resonances: d 7.5-8.5 region.

21.4 Spectroscopy of Carboxylic Acid Derivatives 29


1H NMR Spectroscopy
• The two groups attached to the amide nitrogen
are not chemically equivalent.

• They are diastereotopic.


• Although these groups rotate at ~10 s-1, on the
NMR time scale these groups appear frozen in
position

21.4 Spectroscopy of Carboxylic Acid Derivatives 30


13C NMR Spectroscopy
• C=O: d 165-180

• CN: d 115-120

21.4 Spectroscopy of Carboxylic Acid Derivatives 31


Basicity of Carboxylic Acid Derivatives
• Like carboxylic acids, their derivatives are also
weakly basic.
• Protonation occurs on the carbonyl oxygen.

21.5 Basicity of Carboxylic Acid Derivatives 32


Basicity of Carboxylic Acid Derivatives
• Amides are considerably more basic.

• Nitriles are extremely weak bases.

21.5 Basicity of Carboxylic Acid Derivatives 33


Reactions of Carboxylic Acid Derivatives
There are three general categories:
1. Reactions at the carbonyl (or cyano) group.
a. at the C=O oxygen or CN nitrogen
b. at the C=O carbon or CN carbon
1. Reactions involving the a-carbon.
2. Reactions at the nitrogen of amides.

21.6 Introduction to the Reactions of Carboxylic Acid Derivatives 34


Reactions of Carboxylic Acid Derivatives
• Acyl substitution: Substitution at the carbonyl
carbon.

• Addition is a typical reaction of nitriles:

21.6 Introduction to the Reactions of Carboxylic Acid Derivatives 35


Hydrolysis of Esters
• Saponification – ester hydrolysis in aqueous
hydroxide.

• Saponification is used in the production of soaps


from fats.
• Classified as a nucleophilic acyl substitution

21.7 Hydrolysis of Carboxylic Acid Derivatives 36


Hydrolysis of Esters
• Saponification is effectively irreversible.

21.7 Hydrolysis of Carboxylic Acid Derivatives 37


Hydrolysis of Esters
Acid-catalyzed hydrolysis
•The reaction is slow and requires an excess of
water.

21.7 Hydrolysis of Carboxylic Acid Derivatives 38


Hydrolysis of Esters

• Acid catalyzed ester hydrolysis is classified as a


nucleophilic acyl substitution.

21.7 Hydrolysis of Carboxylic Acid Derivatives 39


Geometry of Nucleophilic Acyl Substitution

21.7 Hydrolysis of Carboxylic Acid Derivatives 40


Hydrolysis and Formation of Lactones
• Because lactones are cyclic esters, they undergo
the reactions of esters.

21.7 Hydrolysis of Carboxylic Acid Derivatives 41


Hydrolysis of Amides
• Amides can be hydrolyzed to carboxylic acids and
ammonia or amines by heating in acidic or basic
solution.

• In acid, protonation of the ammonia or amine


product drives the hydrolysis equilibrium to
completion.

21.7 Hydrolysis of Carboxylic Acid Derivatives 42


Hydrolysis of Amides
• The amine can be isolated, if desired, by addition
of base following the hydrolysis.

• The hydrolysis of amides in base is analogous to


the saponification of ester.

21.7 Hydrolysis of Carboxylic Acid Derivatives 43


Hydrolysis of Nitriles
• Nitriles are hydrolyzed to carboxylic acids and
ammonia by heating them in strongly acidic or
strongly basic solution.

21.7 Hydrolysis of Carboxylic Acid Derivatives 44


Hydrolysis of Nitriles
• Imidic acids can be viewed as the nitrogen-analogs
of enols.

• Base-promoted hydrolysis is also possible.

21.7 Hydrolysis of Carboxylic Acid Derivatives 45


Hydrolysis of Nitriles

21.7 Hydrolysis of Carboxylic Acid Derivatives 46


Hydrolysis of Acid Chlorides and Anhydrides
• Both react rapidly with water, even in the absence
of acids or bases.

21.7 Hydrolysis of Carboxylic Acid Derivatives 47


Nucleophilic Acyl Substitution Reactions

• The conditions for the hydrolysis of these derivatives


can differ considerably.
• The rate-limiting steps can differ for different
derivatives.
21.7 Hydrolysis of Carboxylic Acid Derivatives 48
Carboxylic Acid Derivative Reactivity
• The major factor in the stability of the carbonyl
compound is the resonance interaction of the
potential leaving group X with the carbonyl group.

21.7 Hydrolysis of Carboxylic Acid Derivatives 49


Carboxylic Acid Derivative Reactivity
• Considering the stabilization of the carbonyl
compound, we conclude the reactivity order of the
various derivatives should be the following:

21.7 Hydrolysis of Carboxylic Acid Derivatives 50


Carboxylic Acid Derivative Reactivity
• The polar effect of the leaving group X on the
stability of the transition state should also be
considered.

• The polar effect and resonance effect are reinforcing


effects.

21.7 Hydrolysis of Carboxylic Acid Derivatives 51


Carboxylic Acid Derivative Reactivity

21.7 Hydrolysis of Carboxylic Acid Derivatives 52


Reactions of Acid Chlorides with Nucleophiles
Ammonia and Amines as the Nucleophile

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 53


Reactions of Acid Chlorides with Nucleophiles
Mechanism

•Unless another base is added to the reaction


mixture, the starting amine acts as the base in the
final step.

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 54


Reactions of Acid Chlorides with Nucleophiles
Alcohols and Phenols as the Nucleophile

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 55


Reactions of Acid Chlorides with Nucleophiles
• Sulfonate esters are prepared by the analogous
reactions of sulfonyl chlorides with alcohols.

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 56


Reactions of Acid Chlorides with Nucleophiles
Carboxylate Salts as the Nucleophile

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 57


Reactions of Anhydrides with Nucleophiles

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 58


Reactions of Esters with Nucleophiles
• Amide Formation:

• Hydroxamic Acid Formation:

• Transesterification:

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 59


Penicillin
• Penicillin inhibits transpeptidase (TP), an
important bacterial enzyme involved in the
construction of cell walls.

• TP catalyzes the formation of amide bonds in


peptidoglycan, a component of the cell walls.
21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 60
Penicillin
• In the first step of peptidoglycan synthesis, the –
OH of serine acts as a nucleophile toward the
terminal amide bond in a cell-wall precursor
protein, PG1.

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 61


Penicillin
• In the second step, the ester undergoes an
aminolysis with an amino of PG2.
• This process generates the completed
peptidoglycan linkage of the cell wall.

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 62


Penicillin
• The inhibition of transpeptidase by penicillin
blocks the cell wall biosynthesis.
• This inhibition occurs because the transpeptidase
serine reacts at the carbonyl of the b-lactam.

21.8 Reactions of Carboxylic Acid Derivatives with Nucleophiles 63


Reduction of Esters to Primary Alcohols

• The ester is first reduced to an aldehyde, which is


subsequently reduced to the alcohol.

21.9 Reduction of Carboxylic Acid Derivatives 64


Reduction of Amides to Amines

• Note that a protonolysis step with aqueous acid


follows the LiAlH4 reduction.
• This is followed by base to free the amine.

21.9 Reduction of Carboxylic Acid Derivatives 65


Reduction of Amides to Amines
• Note how the amide reduction differs from that of
ester reduction.

21.9 Reduction of Carboxylic Acid Derivatives 66


Reduction of Amides to Amines
Mechanism

21.9 Reduction of Carboxylic Acid Derivatives 67


Reduction of Amides to Amines
Mechanism (continued)

21.9 Reduction of Carboxylic Acid Derivatives 68


Reduction of Nitriles to Primary Amines

• Two successive nucleophilic additions occur

21.9 Reduction of Carboxylic Acid Derivatives 69


Reduction of Nitriles to Primary Amines

• Nitriles are also reduced by catalytic hydrogenation


using Raney nickel.

21.9 Reduction of Carboxylic Acid Derivatives 70


Reduction of Acid Chlorides to Aldehydes
• The Rosenmund reduction:

21.9 Reduction of Carboxylic Acid Derivatives 71


Reduction of Acid Chlorides to Aldehydes
• Use of derivatives of LiAlH4:

21.9 Reduction of Carboxylic Acid Derivatives 72


Relative Reactivities

• This reactivity order explains why the LAH


reduction of an ester does not stop at the
aldehyde intermediate.
• The aldehyde that is formed is more reactive than
the ester.

21.9 Reduction of Carboxylic Acid Derivatives 73


Reactions of Esters with Grignard Reagents

21.10 Reactions of Carboxylic Acid Derivatives with Organometallic Reagents 74


Reactions of Acid Chlorides with R2CuLi
• Dialkylcuprates are less reactive than Grignard
reagents.

21.10 Reactions of Carboxylic Acid Derivatives with Organometallic Reagents 75


Summary of C.A. Derivative Preparation
Synthesis of esters:
• Acid-catalyzed esterification of RCO2H
• Alkylation of RCO2H or RCO2-
• Acid chlorides or anhydrides with ROH
• Transesterification

Synthesis of acid chlorides:


• RCO2H with SOCl2 or PCl5

21.11 Synthesis of Carboxylic Acid Derivatives 76


Summary of C.A. Derivative Preparation
Synthesis of anhydrides:
• RCO2H with dehydrating agents
• Acid chlorides with RCO2-
Synthesis of amides:
• Acid chlorides, anhydrides, or esters with amines
Synthesis of nitriles:
• Cyanohydrin formation
• SN2 reaction of cyanide ion with alkyl halides or
sulfonate esters

21.11 Synthesis of Carboxylic Acid Derivatives 77


Nylon and Polyesters
• Nylon is a general name given to a group of
polyamides.

21.12 Use and Occurrence of Carboxylic Acids and Their Derivatives 78


Nylon and Polyesters
• Polyesters are condensation polymers derived
from diols and dicarboxylic acids.

21.12 Use and Occurrence of Carboxylic Acids and Their Derivatives 79


Proteins
• Proteins are naturally occurring condensation
polymers of alpha-amino acids.

21.12 Use and Occurrence of Carboxylic Acids and Their Derivatives 80


Waxes, Fats, and Phospholipids
• A wax is an ester of a fatty
acid and a “fatty alcohol.”

• A fat is derived form a


molecule of glycerol and
three molecules of fatty
acid.

21.12 Use and Occurrence of Carboxylic Acids and Their Derivatives 81


Waxes, Fats, and Phospholipids
• Fats with no double bonds are called saturated
fats.
• Fats containing double bonds are called
unsaturated fats.
• Treatment of fats with KOH or NaOH gives glycerol
and the salt of the fatty acid (a soap).
• This reaction is the origin of the term
saponification.

21.12 Use and Occurrence of Carboxylic Acids and Their Derivatives 82


Waxes, Fats, and Phospholipids
• Phospholipids are also esters of glycerol.
• The key structural difference is the presence of a
polar phosphoric acid derivative

21.12 Use and Occurrence of Carboxylic Acids and Their Derivatives 83


PowerPoint slides for the 5th ed. prepared by:

Eric J. Kantorowski
California Polytechnic State University
San Luis Obispo, CA

PowerPoint slides updated and adapted to the 6th ed. by:

Joshua M. Osbourn
West Virginia University
Morgantown, WV
joshua.osbourn@mail.wvu.edu

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