1. Chapter 17 Carboxylic Acids and Their Derivatives Nucleophilic
Addition–Elimination
at the Acyl Carbon
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1. Introduction
Carboxylic Acid Derivatives
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2. Nomenclature and Physical Properties
2A. Carboxylic Acids
Nomenclature of Carboxylic Acids
Rules
Carboxylic acid as parent (suffix): ending with “–oic acid”
Examples
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2B. Carboxylate Salts
Nomenclature of Carboxylic Salts
Rules
Carboxylate as parent (suffix): ending with “–oate”
Examples
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2C. Acidity of Carboxylic Acids
pKa ~ 4-5
Compare
pKa of H2O ~ 16
pKa of H2CO3 ~ 7
pKa of HF ~ 3
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When comparing acidity of organic compounds, we compare the stability of their conjugate bases. The more stable the conjugate base, the stronger the acid
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The conjugate base B1 is more stable (the anion is more delocalized) than B2 due to resonance stabilization
Thus, A1 is a stronger acid than A2
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Acidity of Carboxylic Acids, Phenols, and Alcohols
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Acidity of Carboxylic Acids, Phenols, and Alcohols
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Acidity of Carboxylic Acids, Phenols, and Alcohols
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12. Acidity of Carboxylic Acids, Phenols, and Alcohols
(NO resonance stabilization)
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Question
You are given three unknown samples: one is benzoic acid, one is phenol, and one is cyclohexyl alcohol. How would you distinguish them by simple chemical tests?
Recall: acidity of
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Stability of conjugate bases
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2D. Dicarboxylic Acids
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2E. Esters
Nomenclature of Esters
Rules
Ester as parent (suffix): ending with “–oate”
Examples
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2F. Carboxylic Anhydrides
Nomenclature of Carboxylic Anhydrides
Rules
Most anhydrides are named by dropping the word acid from the name of the carboxylic acid and then adding the word “anhydride”
Example
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2G. Acyl Chlorides
Nomenclature of Acid chlorides
Rules
Acid chloride as parent (suffix): ending with “–oyl chloride”
Example
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2H. Amides
Nomenclature of Amides
Rules
Amide as parent (suffix): ending with “amide”
Example
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2I. Nitriles
Nomenclature of Nitriles
Rules
Nitrile as parent (suffix): ending with “nitrile”
Example
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3. Preparation of Carboxylic Acids
By oxidative cleavage of alkenes
Using KMnO4
Using ozonolysis
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By oxidation of aldehydes & 1o alcohols
e.g.
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By oxidation of alkyl benzene
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By oxidation of benzene ring
e.g.
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By hydrolysis of cyanohydrins and other nitriles
e.g.
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By carbonation of Grignard reagents
e.g.
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4. Acyl Substitution: Nucleophilic Addition-Elimination at the Acyl Carbon
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This nucleophilic acyl substitution occurs through a nucleophilic addition-elimination mechanism
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This type of nucleophilic acyl substitution reaction is common for carboxylic acids and their derivatives
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33. Unlike carboxylic acids and their derivatives, aldehydes and ketones usually do not undergo this type of nucleophilic acyl substitution, due to the lack of an acyl leaving group
A good leaving group
Not a good leaving group
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4A. Relative Reactivity of Acyl Compounds
Relative reactivity of carboxylic acid derivatives towards nucleophilic acyl substitution reactions
There are 2 steps in a nucleophilic acyl substitution
The addition of the nucleophile to the carbonyl group
The elimination of the leaving group in the tetrahedral intermediate
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Usually the addition step (the first step) is the rate-determining step (r.d.s.). As soon as the tetrahedral intermediate is formed, elimination usually occurs spontaneously to regenerate the carbonyl group
Thus, both steric and electronic factors that affect the rate of the addition of a nucleophile control the reactivity of the carboxylic acid derivative
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Steric factor
Electronic factor
The strongly polarized acid derivatives react more readily than less polar ones
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Thus, reactivity of
An important consequence of this reactivity
It is usually possible to convert a more reactive acid derivative into a less reactive one, but not vice versa
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4B. Synthesis of Acid Derivatives
In general, less reactive acyl compounds can be synthesized from more reactive ones, but the reverse is usually difficult and, when possible, requires special reagents.
Synthesis of acid derivatives by acyl substitution requires that the reactant have a better leaving group at the acyl carbon than the product.
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5. Acyl Chlorides
5A. Synthesis of Acyl Chlorides
Conversion of carboxylic acids to acid chlorides
Common reagents
SOCl2
(COCl)2
PCl3 or PCl5
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Mechanism
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5B. Reactions of Acyl Chlorides
Nucleophilic acyl substitution reactions of acid chlorides
Conversion of acid chlorides to carboxylic acids
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Mechanism
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Conversion of acid chlorides to other carboxylic derivatives
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6. Carboxylic Acid Anhydrides
6A. Synthesis of Carboxylic Acid Anhydrides
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6B. Reactions of Carboxylic Acid Anhydrides
Conversion of acid anhydrides to carboxylic acids
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Mechanism
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Conversion of acid anhydrides to other carboxylic derivatives
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7. Esters
7A. Synthesis of Esters: Esterification
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Mechanism
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Esters from acyl chlorides
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Esters from carboxylic acid anhydrides
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7B. Base-Promoted Hydrolysis of Esters: Saponification
Hydrolysis of esters under basic conditions: saponification
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Mechanism
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Hydrolysis of esters under acidic conditions
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Mechanism
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7C. Lactones
Carboxylic acids whose molecules have a hydroxyl group on a g or d carbon undergo an intramolecular esterification to give cyclic esters known as g- or d-lactones
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Lactones are hydrolyzed by aqueous base just as other esters are
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8. Amides
8A. Synthesis of Amides
Amides can be prepared in a variety of ways, starting with acyl chlorides, acid anhydrides, esters, carboxylic acids, and carboxylate salts.
All of these methods involve nucleophilic addition–elimination reactions by ammonia or an amine at an acyl carbon.
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8B. Amides from Acyl Chlorides
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8C. Amides from Carboxylic Anhydrides
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8D. Amides from Esters
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8E. Amides from Carboxylic Acids and Ammonium Carboxylates
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DCC-Promoted amide synthesis
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Mechanism
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Mechanism (Cont’d)
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8F. Hydrolysis of Amides
Acid hydrolysis of amides
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Mechanism
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Basic hydrolysis of amides
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Mechanism
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8G. Nitriles from the Dehydration of Amides
This is a useful synthetic method for preparing nitriles that are not available by nucleophilic substitution reactions between alkyl halides and cyanide ions
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e.g.
dehydration
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Example
Synthesis of
1o alkyl bromide
SN2 reaction with ⊖CN works fine
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But synthesis of
3o alkyl bromide
 No SN2 reaction
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Solution
dehydration
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8H. Hydrolysis of Nitriles
Catalyzed by both acid and base
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Examples
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protonated nitrile
Mechanism
amide
tautomer
protonated
amide
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Mechanism
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8I. Lactams
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9. Derivatives of Carbonic Acid
9A. Alkyl Chloroformates and Carbamates (Urethanes)
Alkyl chloroformate
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e.g.
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Carbamates or urethanes
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Protection
protected amine
Deprotection
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10. Decarboxylation of Carboxylic Acids
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There are two reasons for this ease of decarboxylation
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10A. Decarboxylation of Carboxyl Radicals
Although the carboxylate ions (RCO2‾) of simple aliphatic acids do not decarboxylate readily, carboxyl radicals (RCO2•) do. They decarboxylate by losing CO2 and producing alkyl radicals:
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11. Chemical Tests for Acyl Compounds
Recall: acidity of
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13. Summary of the Reactions of Carboxylic Acids and Their Derivatives
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Reactions of acyl chlorides
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Reactions of acyl chlorides (Cont’d)
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Reactions of acid anhydrides
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Reactions of esters
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Reactions of nitriles
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Reactions of amides
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