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

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

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

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

© 2014 by John Wiley & Sons, Inc. All rights reserved. 2C. Acidity of Carboxylic Acids pKa ~ 4-5 Compare pKa of H2O ~ 16 pKa of H2CO3 ~ 7 pKa of HF ~ 3 © 2014 by John Wiley & Sons, Inc. All rights reserved.

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

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

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

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

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

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

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

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

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

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

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

© 2014 by John Wiley & Sons, Inc. All rights reserved. 3. Preparation of Carboxylic Acids By oxidative cleavage of alkenes Using KMnO4 Using ozonolysis © 2014 by John Wiley & Sons, Inc. All rights reserved.

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

© 2014 by John Wiley & Sons, Inc. All rights reserved. 5. Acyl Chlorides 5A. Synthesis of Acyl Chlorides Conversion of carboxylic acids to acid chlorides Common reagents SOCl2 (COCl)2 PCl3 or PCl5 © 2014 by John Wiley & Sons, Inc. All rights reserved.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

© 2014 by John Wiley & Sons, Inc. All rights reserved. Example Synthesis of 1o alkyl bromide SN2 reaction with ⊖CN works fine © 2014 by John Wiley & Sons, Inc. All rights reserved.

© 2014 by John Wiley & Sons, Inc. All rights reserved. But synthesis of 3o alkyl bromide  No SN2 reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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