Chapter 17 Carboxylic Acids and Their Derivatives Nucleophilic

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Chapter 17 Carboxylic Acids and Their Derivatives Nucleophilic Addition–Elimination at the Acyl Carbon Created

Chapter 17 Carboxylic Acids and Their Derivatives Nucleophilic Addition–Elimination at the Acyl Carbon Created by Professor William Tam & Dr. Phillis Chang Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.

1. Introduction v Carboxylic Acid Derivatives © 2014 by John Wiley & Sons, Inc.

1. Introduction v Carboxylic Acid Derivatives © 2014 by John Wiley & Sons, Inc. All rights reserved.

2. Nomenclature and Physical Properties 2 A. Carboxylic Acids v Nomenclature of Carboxylic Acids

2. Nomenclature and Physical Properties 2 A. Carboxylic Acids v Nomenclature of Carboxylic Acids ● Rules t Carboxylic acid as parent (suffix): ending with “–oic acid” v Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 B. Carboxylate Salts v Nomenclature of Carboxylic Salts ● Rules t Carboxylate as

2 B. Carboxylate Salts v Nomenclature of Carboxylic Salts ● Rules t Carboxylate as parent (suffix): ending with “–oate” v Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 C. Acidity of Carboxylic Acids p. Ka ~ 4 -5 v Compare ●

2 C. Acidity of Carboxylic Acids p. Ka ~ 4 -5 v Compare ● p. Ka of H 2 O ~ 16 ● p. Ka of H 2 CO 3 ~ 7 ● p. Ka of HF ~ 3 © 2014 by John Wiley & Sons, Inc. All rights reserved.

v When comparing acidity of organic compounds, we compare the stability of their conjugate

v When comparing acidity of organic compounds, we compare the stability of their conjugate bases. The more stable the conjugate base, the stronger the acid © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

v The conjugate base B 1 is more stable (the anion is more delocalized)

v The conjugate base B 1 is more stable (the anion is more delocalized) than B 2 due to resonance stabilization ● Thus, A 1 is a stronger acid than A 2 © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Acidity of Carboxylic Acids, Phenols, and Alcohols © 2014 by John Wiley &

v Acidity of Carboxylic Acids, Phenols, and Alcohols © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Acidity of Carboxylic Acids, Phenols, and Alcohols © 2014 by John Wiley &

v Acidity of Carboxylic Acids, Phenols, and Alcohols © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Acidity of Carboxylic Acids, Phenols, and Alcohols © 2014 by John Wiley &

v Acidity of Carboxylic Acids, Phenols, and Alcohols © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Acidity of Carboxylic Acids, Phenols, and Alcohols (NO resonance stabilization) © 2014 by

v Acidity of Carboxylic Acids, Phenols, and Alcohols (NO resonance stabilization) © 2014 by John Wiley & Sons, Inc. All rights reserved.

Question v You are given three unknown samples: one is benzoic acid, one is

Question v 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 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

> > > Stability of conjugate bases > v © 2014 by John Wiley

> > > Stability of conjugate bases > v © 2014 by John Wiley & Sons, Inc. All rights reserved.

> > > > > © 2014 by John Wiley & Sons, Inc. All

> > > > > © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 D. Dicarboxylic Acids © 2014 by John Wiley & Sons, Inc. All rights

2 D. Dicarboxylic Acids © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 E. Esters v Nomenclature of Esters ● Rules t Ester as parent (suffix):

2 E. Esters v Nomenclature of Esters ● Rules t Ester as parent (suffix): ending with “–oate” v Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 F. Carboxylic Anhydrides v Nomenclature of Carboxylic Anhydrides ● Rules t Most anhydrides

2 F. Carboxylic Anhydrides v Nomenclature of Carboxylic Anhydrides ● Rules t Most anhydrides are named by dropping the word acid from the name of the carboxylic acid and then adding the word “anhydride” v Example © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 G. Acyl Chlorides v Nomenclature of Acid chlorides ● Rules t Acid chloride

2 G. Acyl Chlorides v Nomenclature of Acid chlorides ● Rules t Acid chloride as parent (suffix): ending with “–oyl chloride” v Example © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 H. Amides v Nomenclature of Amides ● Rules t Amide as parent (suffix):

2 H. Amides v Nomenclature of Amides ● Rules t Amide as parent (suffix): ending with “amide” v Example © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 I. Nitriles v Nomenclature of Nitriles ● Rules t Nitrile as parent (suffix):

2 I. Nitriles v Nomenclature of Nitriles ● Rules t Nitrile as parent (suffix): ending with “nitrile” v Example © 2014 by John Wiley & Sons, Inc. All rights reserved.

3. Preparation of Carboxylic Acids v By oxidative cleavage of alkenes ● Using KMn.

3. Preparation of Carboxylic Acids v By oxidative cleavage of alkenes ● Using KMn. O 4 ● Using ozonolysis © 2014 by John Wiley & Sons, Inc. All rights reserved.

v By oxidation of aldehydes & 1 o alcohols ● e. g. © 2014

v By oxidation of aldehydes & 1 o alcohols ● e. g. © 2014 by John Wiley & Sons, Inc. All rights reserved.

v By oxidation of alkyl benzene © 2014 by John Wiley & Sons, Inc.

v By oxidation of alkyl benzene © 2014 by John Wiley & Sons, Inc. All rights reserved.

v By oxidation of benzene ring ● e. g. © 2014 by John Wiley

v By oxidation of benzene ring ● e. g. © 2014 by John Wiley & Sons, Inc. All rights reserved.

v By hydrolysis of cyanohydrins and other nitriles ● e. g. © 2014 by

v By hydrolysis of cyanohydrins and other nitriles ● e. g. © 2014 by John Wiley & Sons, Inc. All rights reserved.

v By carbonation of Grignard reagents ● e. g. © 2014 by John Wiley

v By carbonation of Grignard reagents ● e. g. © 2014 by John Wiley & Sons, Inc. All rights reserved.

4. Acyl Substitution: Nucleophilic Addition-Elimination at the Acyl Carbon © 2014 by John Wiley

4. Acyl Substitution: Nucleophilic Addition-Elimination at the Acyl Carbon © 2014 by John Wiley & Sons, Inc. All rights reserved.

v This nucleophilic acyl substitution occurs through a nucleophilic additionelimination mechanism © 2014 by

v This nucleophilic acyl substitution occurs through a nucleophilic additionelimination mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v This type of nucleophilic acyl substitution reaction is common for carboxylic acids and

v This type of nucleophilic acyl substitution reaction is common for carboxylic acids and their derivatives © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Unlike carboxylic acids and their derivatives, aldehydes and ketones usually do not undergo

v 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 © 2014 by John Wiley & Sons, Inc. All rights reserved.

4 A. Relative Reactivity of Acyl Compounds v Relative reactivity of carboxylic acid derivatives

4 A. Relative Reactivity of Acyl Compounds v Relative reactivity of carboxylic acid derivatives towards nucleophilic acyl substitution reactions ● There are 2 steps in a nucleophilic acyl substitution t The addition of the nucleophile to the carbonyl group t The elimination of the leaving group in the tetrahedral intermediate © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Usually the addition step (the first step) is the rate-determining step (r. d.

● 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 © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Steric factor ● Electronic factor t The strongly polarized acid derivatives react more

● Steric factor ● Electronic factor t The strongly polarized acid derivatives react more readily than less polar ones © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Thus, reactivity of ● An important consequence of this reactivity t It is

● Thus, reactivity of ● An important consequence of this reactivity t It is usually possible to convert a more reactive acid derivative into a less reactive one, but not vice versa © 2014 by John Wiley & Sons, Inc. All rights reserved.

4 B. Synthesis of Acid Derivatives v In general, less reactive acyl compounds can

4 B. Synthesis of Acid Derivatives v 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. v Synthesis of acid derivatives by acyl substitution requires that the reactant have a better leaving group at the acyl carbon than the product. © 2014 by John Wiley & Sons, Inc. All rights reserved.

5. Acyl Chlorides 5 A. Synthesis of Acyl Chlorides v Conversion of carboxylic acids

5. Acyl Chlorides 5 A. Synthesis of Acyl Chlorides v Conversion of carboxylic acids to acid chlorides ● Common reagents t SOCl 2 t (COCl)2 t PCl 3 or PCl 5 © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

5 B. Reactions of Acyl Chlorides v Nucleophilic acyl substitution reactions of acid chlorides

5 B. Reactions of Acyl Chlorides v Nucleophilic acyl substitution reactions of acid chlorides ● Conversion of acid chlorides to carboxylic acids © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Conversion of acid chlorides to other carboxylic derivatives © 2014 by John Wiley

● Conversion of acid chlorides to other carboxylic derivatives © 2014 by John Wiley & Sons, Inc. All rights reserved.

6. Carboxylic Acid Anhydrides 6 A. Synthesis of Carboxylic Acid Anhydrides © 2014 by

6. Carboxylic Acid Anhydrides 6 A. Synthesis of Carboxylic Acid Anhydrides © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

6 B. Reactions of Carboxylic Acid Anhydrides v Conversion of acid anhydrides to carboxylic

6 B. Reactions of Carboxylic Acid Anhydrides v Conversion of acid anhydrides to carboxylic acids © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

● Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Conversion of acid anhydrides to other carboxylic derivatives © 2014 by John Wiley

v Conversion of acid anhydrides to other carboxylic derivatives © 2014 by John Wiley & Sons, Inc. All rights reserved.

7. Esters 7 A. Synthesis of Esters: Esterification © 2014 by John Wiley &

7. Esters 7 A. Synthesis of Esters: Esterification © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Esters from acyl chlorides © 2014 by John Wiley & Sons, Inc. All

v Esters from acyl chlorides © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Esters from carboxylic acid anhydrides © 2014 by John Wiley & Sons, Inc.

v Esters from carboxylic acid anhydrides © 2014 by John Wiley & Sons, Inc. All rights reserved.

7 B. Base-Promoted Hydrolysis of Esters: Saponification v Hydrolysis of esters under basic conditions:

7 B. Base-Promoted Hydrolysis of Esters: Saponification v Hydrolysis of esters under basic conditions: saponification © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Hydrolysis of esters under acidic conditions © 2014 by John Wiley & Sons,

v Hydrolysis of esters under acidic conditions © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

7 C. Lactones v Carboxylic acids whose molecules have a hydroxyl group on a

7 C. Lactones v 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 © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Lactones are hydrolyzed by aqueous base just as other esters are © 2014

v Lactones are hydrolyzed by aqueous base just as other esters are © 2014 by John Wiley & Sons, Inc. All rights reserved.

8. Amides 8 A. Synthesis of Amides v Amides can be prepared in a

8. Amides 8 A. Synthesis of Amides v Amides can be prepared in a variety of ways, starting with acyl chlorides, acid anhydrides, esters, carboxylic acids, and carboxylate salts. v All of these methods involve nucleophilic addition–elimination reactions by ammonia or an amine at an acyl carbon. © 2014 by John Wiley & Sons, Inc. All rights reserved.

8 B. Amides from Acyl Chlorides © 2014 by John Wiley & Sons, Inc.

8 B. Amides from Acyl Chlorides © 2014 by John Wiley & Sons, Inc. All rights reserved.

8 C. Amides from Carboxylic Anhydrides © 2014 by John Wiley & Sons, Inc.

8 C. Amides from Carboxylic Anhydrides © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

8 D. Amides from Esters © 2014 by John Wiley & Sons, Inc. All

8 D. Amides from Esters © 2014 by John Wiley & Sons, Inc. All rights reserved.

8 E. Amides from Carboxylic Acids and Ammonium Carboxylates © 2014 by John Wiley

8 E. Amides from Carboxylic Acids and Ammonium Carboxylates © 2014 by John Wiley & Sons, Inc. All rights reserved.

v DCC-Promoted amide synthesis © 2014 by John Wiley & Sons, Inc. All rights

v DCC-Promoted amide synthesis © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism (Cont’d) © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism (Cont’d) © 2014 by John Wiley & Sons, Inc. All rights reserved.

8 F. Hydrolysis of Amides v Acid hydrolysis of amides © 2014 by John

8 F. Hydrolysis of Amides v Acid hydrolysis of amides © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Basic hydrolysis of amides © 2014 by John Wiley & Sons, Inc. All

v Basic hydrolysis of amides © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

8 G. Nitriles from the Dehydration of Amides v This is a useful synthetic

8 G. Nitriles from the Dehydration of Amides v This is a useful synthetic method for preparing nitriles that are not available by nucleophilic substitution reactions between alkyl halides and cyanide ions © 2014 by John Wiley & Sons, Inc. All rights reserved.

v e. g. dehydration © 2014 by John Wiley & Sons, Inc. All rights

v e. g. dehydration © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Example ● Synthesis of 1 o alkyl bromide SN 2 reaction with ⊖CN

v Example ● Synthesis of 1 o alkyl bromide SN 2 reaction with ⊖CN works fine © 2014 by John Wiley & Sons, Inc. All rights reserved.

But synthesis of 3 o alkyl bromide No SN 2 reaction © 2014 by

But synthesis of 3 o alkyl bromide No SN 2 reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

Solution dehydration © 2014 by John Wiley & Sons, Inc. All rights reserved.

Solution dehydration © 2014 by John Wiley & Sons, Inc. All rights reserved.

8 H. Hydrolysis of Nitriles v Catalyzed by both acid and base © 2014

8 H. Hydrolysis of Nitriles v Catalyzed by both acid and base © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism protonated nitrile amide tautomer protonated amide © 2014 by John Wiley &

v Mechanism protonated nitrile amide tautomer protonated amide © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism © 2014 by John Wiley & Sons, Inc. All rights reserved.

8 I. Lactams © 2014 by John Wiley & Sons, Inc. All rights reserved.

8 I. Lactams © 2014 by John Wiley & Sons, Inc. All rights reserved.

9. Derivatives of Carbonic Acid 9 A. Alkyl Chloroformates and Carbamates (Urethanes) v Alkyl

9. Derivatives of Carbonic Acid 9 A. Alkyl Chloroformates and Carbamates (Urethanes) v Alkyl chloroformate © 2014 by John Wiley & Sons, Inc. All rights reserved.

v e. g. © 2014 by John Wiley & Sons, Inc. All rights reserved.

v e. g. © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Carbamates or urethanes © 2014 by John Wiley & Sons, Inc. All rights

v Carbamates or urethanes © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Protection v Deprotection protected amine © 2014 by John Wiley & Sons, Inc.

v Protection v Deprotection protected amine © 2014 by John Wiley & Sons, Inc. All rights reserved.

10. Decarboxylation of Carboxylic Acids © 2014 by John Wiley & Sons, Inc. All

10. Decarboxylation of Carboxylic Acids © 2014 by John Wiley & Sons, Inc. All rights reserved.

v There are two reasons for this ease of decarboxylation © 2014 by John

v There are two reasons for this ease of decarboxylation © 2014 by John Wiley & Sons, Inc. All rights reserved.

10 A. Decarboxylation of Carboxyl Radicals v Although the carboxylate ions (RCO 2‾) of

10 A. Decarboxylation of Carboxyl Radicals v Although the carboxylate ions (RCO 2‾) of simple aliphatic acids do not decarboxylate readily, carboxyl radicals (RCO 2 • ) do. They decarboxylate by losing CO 2 and producing alkyl radicals: © 2014 by John Wiley & Sons, Inc. All rights reserved.

11. Chemical Tests for Acyl Compounds v Recall: acidity of © 2014 by John

11. Chemical Tests for Acyl Compounds v Recall: acidity of © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved.

13. Summary of the Reactions of Carboxylic Acids and Their Derivatives © 2014 by

13. Summary of the Reactions of Carboxylic Acids and Their Derivatives © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Reactions of acyl chlorides © 2014 by John Wiley & Sons, Inc. All

v Reactions of acyl chlorides © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Reactions of acyl chlorides (Cont’d) © 2014 by John Wiley & Sons, Inc.

v Reactions of acyl chlorides (Cont’d) © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Reactions of acid anhydrides © 2014 by John Wiley & Sons, Inc. All

v Reactions of acid anhydrides © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Reactions of esters © 2014 by John Wiley & Sons, Inc. All rights

v Reactions of esters © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Reactions of nitriles © 2014 by John Wiley & Sons, Inc. All rights

v Reactions of nitriles © 2014 by John Wiley & Sons, Inc. All rights reserved.

v Reactions of amides © 2014 by John Wiley & Sons, Inc. All rights

v Reactions of amides © 2014 by John Wiley & Sons, Inc. All rights reserved.