Chapter 20
Carboxylic Acids and Their Derivatives:
Nucleophilic Acyl Substitution
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Chapter 20 Problem Set
11 39abcdefg jkl
13 40
15 42
16 43
18 47
19 56
57
60
65
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Carboxylic Acid Derivatives
This chapter focuses on carbonyl compounds with groups that can be replaced by a nucleophile
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Nomenclature
acetic acid benzoic acid ethyl acetate ethyl benzoate
acetyl chloride benzoyl chloride acetamide benzamide
acetonitrile benzonitrile
acetic anhydride benzoic anhydride acetic benzoic
anhydride
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Properties of Carboxylic Acid Derivatives
Amide bonds form proteins
Some esters have pleasant odor
Amides form NH•••O hydrogen bonds
Esters in natural products
Lactams (cyclic amides) in drugs and antibiotics
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Resonance of Carboxylic Acid Derivatives
Conj. acid HCl RCO2H H2O R’OH NH3
pKa –7 3–5 15.7 15.5-18 38
Better leaving group
As the basicity of Z increases, the
stability of RCOZ increases because of
added resonance stabilization.
More reactive compounds can be converted
into less reactive ones. 6
Nucleophilic Acyl Substitutions
Z: leaving group Z should be a better leaving group than Nu
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Nucleophilic Acyl Substitution of Acid Chlorides
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Nucleophilic Acyl Substitution of Acid Chlorides
• 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.
<mechanism>
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Nucleophilic Acyl Substitution of Anhydrides
Anhydrides are somewhat less reactive than acid chlorides, but still readily react with most nucleophiles.
amide formation
ester formation
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Anhydrides Use in Acetylation Reactions
• Reactions that result in the transfer of an acetyl group are known as acetylations.
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Acyl Substitution Reactions of Carboxylic Acids
Very difficult
impractical
Easier
practical
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Formation of Acyl Halides
• Treatment of a carboxylic acid with thionyl chloride (SOCl2) affords an acid chloride.
• This is possible because thionyl chloride converts the OH group of the acid into a better leaving group, and
because it provides the nucleophile (Cl¯) to displace the leaving group.
<Mechanism>
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Dehydration of Carboxylic Acids
• Although carboxylic acids cannot readily be converted into anhydrides, dicarboxylic acids
can be converted to cyclic anhydrides by heating to high temperatures.
• This is a dehydration reaction because a water molecule is lost from the diacid.
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Fischer Esterification of Carboxylic Acids
• Fischer esterification: Treatment of a carboxylic acid with an alcohol in the presence of an acid
catalyst forms an ester. (Using base does not work!)
• Reaction is an equilibrium. Driven by excess alcohol or by removing water as it is formed.
<Mechanism>
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Amide Formation from Carboxylic Acids
Requires high temperature (>100 °C), slow rxn, low yields – impractical
1. Stepwise reaction
2. Single-step reaction with dicyclohexylcarbodimide (DCC)
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DCC in Amide Formation
<Mechanism>
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Reactions of Esters
• Esters are hydrolyzed with water in the presence of either acid or base to form carboxylic acids or
carboxylate anions, respectively.
• Esters react with NH3 and amines to form 1°, 2°, or 3° amides.
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Base Hydrolysis of Esters
• 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.
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Base Hydrolysis of Esters
• Hydrolysis is base promoted. Not base catalyzed.
• OH– is the nucleophile. Not regenerated
• Making soap
Hydrolysis of triacylglycerol → forms amphiphilic carboxylate salts
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Amide Hydrolysis
• Amides are the least reactive of the carboxylic • In acid, the amine by-product is protonated as
acid derivatives. an ammonium ion, whereas in base, a neutral
• Amides are hydrolyzed in acid or base to form amine forms.
carboxylic acids or carboxylate anions.
<Mechanism>
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-Lactam Antibiotics
• Penicillin and related -lactams kill bacteria by a nucleophilic acyl substitution reaction.
• The -lactam is more reactive than other amides because it is part of a strained, four
membered ring that is readily opened with nucleophiles.
• A nucleophilic OH group of the glycopeptide transpeptidase enzyme cleaves the -lactam ring of
penicillin by a nucleophilic acyl substitution reaction.
• The reaction causes covalent modification of the enzyme, thus inactivating it and halting cell wall
construction killing the bacterium.
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Summary of Nucleophilic Substitution Reactions
Better leaving group
More stable product
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Fibers
• Natural fibers
• Synthetic fibers
Nylon - polyamide Polyester
Nylon synthesis demo
https://www.youtube.com/watch?v=lNWc6xUf6U4
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Reactions of Nitriles
• Nitriles are prepared by SN2 reactions of unhindered methyl and 1° alkyl halides with ¯CN.
• Nitriles will react with water, hydride and organometallics.
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Hydrolysis of Nitriles
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LAH Reduction of Nitriles
• Treatment of a nitrile with LiAlH4 (LAH) followed by H2O adds two equivalents of H2
across the triple bond, forming a 1o amine.
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DIBAL Reduction of Nitriles
• Treatment of a nitrile with a milder reducing agent such as DIBAL-H (DIBAL)
followed by water forms an aldehyde.
<Mechanism>
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Reduction of Nitriles with Organometallics
• Both Grignard and organolithium reagents react with nitriles to form ketones with a new C–C bond.
<Mechanism>
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Spectroscopic Properties—IR
• Carboxylic acid derivatives have a strong C=O absorption between 1600 and 1850 cm−1.
• Primary (1°) and 2° amides have two additional absorptions due to N–H bonds:
1. One or two N–H stretching peaks at 3200–3400 cm−1.
2. An N–H bending absorption at ~1640 cm−1.
• As the carbonyl bond becomes more delocalized, the C=O absorption shifts to lower frequency.
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Spectroscopic Properties—NMR
• Protons on the carbon: 2–2.5 ppm.
• The NH protons of amides: 7.5–8.5 ppm.
• Carboxylic acid derivatives give a highly
deshielded peak at 160–180 ppm due to the
carbonyl carbon.
(less downfield than aldehydes and ketones)
• Nitriles give a peak at 115–120 ppm
sp hybridized carbon,
more downfield than alkynes
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