Carboxylic Acids and Nitriles...79 •LiAlH 4 is a strong reducing agent that reduces acids, acid...
Transcript of Carboxylic Acids and Nitriles...79 •LiAlH 4 is a strong reducing agent that reduces acids, acid...
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Carboxylic Acids and Nitriles
Chapters 20, 21
Organic Chemistry, 8th Edition
John McMurry
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Carboxylic Acid Derivatives
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Carboxylic Acid Derivatives
nitrile R = CH3
acetonitrile
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Structure and Bonding
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Nomenclature—The IUPAC System
3-pentenoic
acid 4,5-dimethyl
hexanoic acid 1-methyl-
cyclopropanecarboxylic
acid
heptanoic acid benzoic acid cyclopentane
carboxylic acid
3-bromobenzoic
acid
p-toluic
acid
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Nomenclature-Common Names
(protos=primo + pion=grasso)
Il primo degli acidi grassi
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Nomenclature-Polyiacids
Oxalis acetosella Malon Succinum (ambra)
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Nomenclature-Salts
• To name the metal salt of a carboxylate anion, put three parts together:
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• Carboxylic acids exhibit dipole-dipole interactions because they have polar
C—O and O—H bonds.
• They also exhibit intermolecular hydrogen bonding.
• In the gas phase and in apolar solvents, carboxylic acids often exist as
dimers held together by two intermolecular hydrogen bonds.
Physical Properties
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Physical Properties
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Acidity of Carboxylic Acids
• Because the pKa values of many carboxylic acids are ~5, bases that have conjugate
acids with pKa values higher than 5 are strong enough to deprotonate them.
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• The acetate anion has two C—O bonds of equal length (1.27 Å) and
intermediate between the length of a C—O single bond (1.36 Å) and C=O
(1.21 Å).
Acidity of Carboxylic Acids
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Carboxylic Acids—Strong Organic BrØnsted-
Lowry Acids
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The Inductive Effect in Aliphatic Carboxylic Acids
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The Inductive Effect in Aliphatic Carboxylic Acids
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Substituted Benzoic Acids
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Substituted Benzoic Acids
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Sulfonic Acids
• Sulfonic acids have the general structure RSO3H.
• The most widely used sulfonic acid is p-toluenesulfonic acid.
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Preparation of Carboxylic Acids
[1] Oxidation of 1° alcohols
[2] Oxidation of alkyl benzenes
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[3] From alkyl halides
Preparation of Carboxylic Acids
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[3] Oxidative cleavage of alkynes
Preparation of Carboxylic Acids
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Reactions of Carboxylic Acids
acyl chloride
anhydride
ester
amide
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Derivatives: Structure and Bonding
• Three resonance structures stabilize carboxylic acid derivatives (RCOZ)
by delocalizing electron density.
stability
reactivity
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Derivatives: Physical Properties
• Because all carbonyl compounds have a polar carbonyl group, they
exhibit dipole-dipole interactions.
• Because they contain one or two N—H bonds, 1° and 2° amides are
capable of intermolecular hydrogen bonding.
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MW = 60 bp 118 °C
Derivatives: Physical Properties
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Reaction of Carboxylic Acid Derivatives:
Nucleophilic Acyl Substitution
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Introduction to Nucleophilic Acyl Substitution
All derivatives are hydrolysed
to carboxylic acids
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Acid Chlorides: Nomenclature
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By the reaction of a carboxylic acid with thionyl chloride (SOCl2).
Acid Chlorides: Synthesis
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• Acyl chlorides are the most reactive among carboxylic acid derivatives
• A weak, non nucleophilic, base like pyridine is often added to the
reaction mixture to remove the byproduct HCl.
Acid Chlorides: Reactions
anhydride
ester
acid
amide
(acid chlorides are readily
decomposed by water)
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Reactions of Acid Chlorides
Hydrolysis:
Formation of anhydrides:
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• Acid chlorides also react with ammonia and 1° and 2° amines to form 1°,
2° and 3° amides respectively.
• Two equivalents of NH3 or amine are used.
• One equivalent acts as the nucleophile to replace Cl, while the other
reacts as a base with the HCl by-product to form an ammonium salt.
Reactions of Acid Chlorides
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• DEET is the active ingredient in the most widely used insect repellents,
and is effective against mosquitoes, fleas and ticks.
Reactions of Acid Chlorides
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Anhydrides
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Anydrides: Nomenclature
acetic
anhydride
benzoic
anhydride
acetic benzoic
anhydride
succinic
anhydride
maleic
anhydride
phthalic
anhydride
succinic
acid
maleic
acid
phthalic
acid
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Anhydrides: Synthesis
1. By dehydration of carboxylic acids at high temperatures (700-800 °C)
and/or in the presence of condensing agents
Formation of cyclic
anhydrides is easier
2. From an acid and an acyl chloride
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Anhydrides: Reactions
• Anhydrides are strong acylating agents a
• A weak acid is formed as by-product.
ester
acid
amide
(anhydrides are readily
decomposed by water)
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Reactions of Anhydrides
Anhydrides are very common acetylating agents for the synthesis of
esters and amides:
(Paracetamol)
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Esters: Nomenclature
Butyrolactone Valerolactone
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Interesting Esters
Many low molecular weight esters have pleasant and very characteristic
odors.
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Lipids
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• Fischer esterification.
Esters from Carboxylic Acids
• SN2 (mainly for methyl esters).
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• The reaction is an equilibrium, so it is driven to the right by
using excess alcohol or by removing water as it is formed.
Fischer Esterification
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Esters: Synthesis
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Esters: Reactions
Acid hydrolysis
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• Basic hydrolysis of an ester is also called saponification.
• Hydrolysis is base promoted, not base catalyzed, because the base
(OH–) is the nucleophile that adds to the ester and forms part of the
product. It participates in the reaction and is not regenerated later.
Esters: Reactions
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• Soap is prepared by the basic hydrolysis or saponification of a
triacylglycerol. Heating an animal fat or vegetable oil with aqueous base
hydrolyzes the three esters to form glycerol and sodium salts of three fatty
acids. These carboxylate salts are soaps.
Lipid Hydrolysis
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Soap • Soap molecules self-aggregate in water to form micelles
sodium laurylsulfate
SDS
• Synthetic detergents
cetyltrimethylammonium
bromide
CTAB
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Esters: Other Reactions
H+, H2O or OH-
H+, ROH or RO-
Mechanism of amide formation
transeserification
acid
amide
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Amides: Structure
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C, N, O: sp2
planar
Restricted rotation
Amide resonance
Trans amides are more stable
than cis amides
Amides: Structure
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Amides: Basicity
pKa = 9
pKa = -1
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• All 1° amides are named by replacing the -ic acid, -oic acid, or -ylic acid
ending with the suffix amide.
• 2° and 3° amides are named as N-substituted (2°) or N,N-disubstituted
(3°) derivatives of 1° amides
Amides: Nomenclature
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An important group of naturally occurring amides consists of proteins,
polymers of amino acids joined together by amide linkages.
Interesting Amides
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Several useful drugs are amides.
Interesting Amides
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• Carboxylic acids cannot be converted into amides by reaction with NH3 or
an amine.
Amides from Carboxylic Acids
• Carboxylic acids are converted into amides by reaction with NH3 or an
amine in the presence of a condensing agent (DCC).
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Reactions of Carboxylic Acids: Amides
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Synthesis of Amides
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• Amides are the least reactive of the carboxylic acid derivatives.
Amides: Reactions
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• The mechanism of amide hydrolysis is exactly the same as the mechanism
of ester hydrolysis.
Amide hydrolysis is hard in acid because the nucleophile (H2O) and
the electrophile (amide) are poor.
Amide hydrolysis is hard in base because the electrophile and the
leaving group (NR2-) are poor.
Amides: Reactions
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Carboxylic acids are reduced to 1° alcohols with LiAlH4.
Mechanism:
Reduction of Carboxylic Acids
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Reduction: acid chlorides, anhydrides
and esters
Z = Cl, OCOR, OR’
• Acid chlorides, anhydrides and esters are reduced to 1ry alcohols by Al
hydrides, e.g. LiAlH4
• A two-step reaction:
1. Nucleophilic acyl substitution
2. Nucleophilic addition
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• LiAlH4 is a strong reducing agent that reduces acids, acid chlorides,
anhydrides and esters to primary alcohols.
• Diisobutylaluminum hydride ([(CH3)2CHCH2]2AlH, abbreviated DIBAL-H,
has two bulky isobutyl groups which makes this reagent less reactive than
LiAlH4.
• DIBAL-H reduces acid chlorides, anhydrides and esters to aldehydes.
Reduction of acid chlorides, anhydrides
and esters
DIBAL-H
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Reduction of acid chlorides, anhydrides
and esters
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Reduction of Carboxylic Acids and Their Derivatives
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Reduction of Amides
• Amides are reduced to amines by Al hydrides, e.g. LiAlH4
• A two-step reaction:
1. Nucleophilic addition-elimination
2. Nucleophilic addition
imminium ion
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Reduction of Amides
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Reaction of Organometallic Reagents with
Carboxylic Acid Derivatives.
• Both esters and acid chlorides form 3° alcohols when treated with two
equivalents of either Grignard or organolithium reagents.
• A two-step reaction:
1. Nucleophilic acyl substitution
2. Nucleophilic addition
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• Organocuprates (R’2CuLi) are less reactive than organolithium and
organomagnesium compounds.
• R’2CuLi react only with acid chlorides, which are the more reactive among
carboxylic acid derivatives, to give a ketone as the product.
• Esters do not react with R’2CuLi.
Reaction of Organometallic Reagents with
Carboxylic Acid Derivatives.
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Reaction of Organometallic Reagents with
Carboxylic Acid Derivatives.
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Reaction of Organometallic Reagents with CO2
• Grignards react with CO2 to give carboxylic acids after protonation with
aqueous acid.
• This reaction is called carboxylation.
• The carboxylic acid formed has one more carbon atom than the Grignard
reagent from which it was prepared.
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Summary: important reactions of acid chlorides.
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Summary: important reactions of anhydrides.
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Summary: important reactions of esters.
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Summary: important reactions of amides.
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Natural and Synthetic Fibers
• Fibers like wool and silk are proteins obtained from animals.
• Cotton and linen are derived from carbohydrates having the general
structure of cellulose.
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Natural and Synthetic Fibers: Nylon—A Polyamide
Nylon 6
monomers: or
monomers: adipic acid hexamethylenediamine
6-aminohexanoic acid -caprolactam
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• Nylon is a condensation polymer
Natural and Synthetic Fibers: Nylon—A Polyamide
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Natural and Synthetic Fibers: Polyesters
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Nitriles
• Nitriles are not common in nature.
• Cianohydrins are the most common nitriles.
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Nomenclature—Nitriles
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Nitriles
• Nitriles are prepared by SN2 reactions of unhindered methyl and 1° alkyl
halides with ¯CN.
• Nitriles are prepared by dehydration of amides (more general).
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Reactions of Nitriles – Nucleophilic
Addition to the CN Group
Nu: = H- ([Al]-H); R- (R-[M]); H2O
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Reactions of Nitriles—Reduction
LiAlH4 (more reactive)
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Reactions of Nitriles—Reduction
DIBAL-H (less reactive)
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Addition of Organometallic reagents
• Both Grignard and organolithium reagents react with nitriles to form
ketones with a new C—C bond.
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Reactions of Nitriles—Hydrolysis
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Reactions of Nitriles—Hydrolysis
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Summary: important reactions of nitriles.