Chapter 14 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution 14.1 Carboxylic Acid Derivatives and Nomenclature 14.2 Structure of carboxylic acid derivatives 14.3 Preparation of carboxylic acid derivatives 14.4 Nucleophilic substitution at the acyl carbon Hydrolysis Reactions with alcohols Reactions with amines

14. 5 Reduction Reduction by LiAlH 4 (LAH) and its derivatives Reduction by Na Reaction with Grignard reagents 14.6 Reactions of amides Dehydration of amides The Hofmann Rearrangement 14.7 Spectroscopic analysis of carboxylic acid derivatives

Propanoyl chloride 丙酰氯 Acyl halides 酰卤 Acetic anhydride 乙酸酐 Carboxylic acid anhydrides 酸 酐酸 酐 Propanoic acid Esters 酯 Acetic acid Ethyl acetate 乙酸乙酯 Acetic acid Propanoyl chloride Acetic anhydride Ethyl acetate P309, 10.1 P309, 10.1 Benzoic acidEthyl benzoate （苯甲酸乙酯） 14.1 Carboxylic Acid Derivatives and Nomenclatures

Acetamide 乙 酰胺 N-Methylbenzamide N- 甲基苯甲 酰胺 N,N-Dimethylform- amide (DMF) N, N- 二甲基甲 酰胺 Amides 酰胺 Acetic acidAcetamide Nitrile 腈 Benzonitrile 苄腈 Phenyl cyanide 苯基氰 Benzoic acid Benzonitrile 4-Methylpentanenitrile 4- 甲基戊腈

R O L A common feature of carboxylic acid derivatives: Hydrolysis to carboxylic acids 14.2 Structure of carboxylic acid derivatives p - π Conjugation +C Effect:

14.3 Preparation of Carboxylic Acid Derivatives Preparation of Acyl Halides SOCl 2 (Thionyl chloride) PBr 3 (Phosphorous tribromide) Preparation of Acid Anhydride

Preparation of Esters Preparation of Amides

14.4 Nucleophilic substitution at the acyl carbon Hydrolysis P318,10.5 Ch.P390

Mechanism: Saponification ( 皂 化 反应 ) Step 1 Nucleophilic addition of hydroxide ion to carbonyl group. Base-promoted hydrolysis of ester Hydrolysis of Acyl halides is catalyzed by a base. Hydrolysis of Acid anhydrides Esters Amides Catalyzed by a acid or a base. P331

Step 2 Elimination of leaving group to restore carbonyl group: Step 3 Proton transfer to yield alcohol and carboxylate ion:

Reactions with alcohols Acyl halides Acid anhydrides Esters Nitriles Alcohols or phenols Esters Hydrolysis of Nitriles: P320 Reactivity of carboxylic acid derivatives:

Benzoyl chlorideEthyl benzoate (80%) Esters Alcohols Esters (Exchange of esters) Salicylic acid ( 水杨酸 ) Asprin ( 阿司匹林 )

Methyl acrylate （丙烯酸甲酯） Butyl alcohol （丁醇） Butyl acrylate ( 丙烯酸丁酯 ) (94%) Alcoholysis of Nitriles: Ch.P391

Benzoyl chloride Piperidine （哌啶） N-Benzoyl- Piperidine （ N- 苯甲酰哌啶） （ 87-91% ） Ethyl Floroacetate （氟乙酸乙酯） Floroacetamide （氟乙酸酰胺） (90%) Reactions with amines Acyl halides Carboxylic acid anhydrides Esters Ammonia or amines Amides

14. 5 Reduction Reduction by LiAlH 4 (LAH) and its derivatives

1) LiAlH(OR) 3 Acyl halides Amides 2) H 2 O Aldehydes Amides Nitriles Amines LiAlH 4 Acryl halides Carboxylic acid Acid anhydrides Esters Primary alcohols LiAlH 4

Reduction by Na Bouveault - Blanc reduction EstersNa Ethanol Butanol Pentanol refluxPrimary alcohols Ethyl oleate 油酸乙酯 Oleic alcohol 油醇 The unique method for the preparation of unsaturated primary alcohols in industry Ch. P393

Reaction with Grignard reagents 1 mol RMgXLow temperature RMgX Ketones Tertiary alcohols Carboxylic acid derivatives RMgX

Reactions of nitriles with Grignard reagents Addition 1. RMgX Imine 亚胺 Nitriles 2. H 2 O Hydrolysis Ketones RLi reacts in the same way and are often used instead of RMgX

14.6 Reactions of amides The dehydration of amides Amides Dehydrating agents: P 4 O 10 (P 2 O 5 ), （脱水剂） (CH 3 CO) 2 O HeatingTo form nitrils 2-Methylpropanamide 2- 甲基丙酰胺 2-Methylpropanenitrile 2- 甲基丙腈 （ 69-86% ）

Br 2 / OH － Carbonyl group had been plucked out The Hofmann Rearrangement （ Hofmann 降解反应 ） N-unsubstituted amides to form primary amines having one less carbon atom than amide Mechanism: Step 1 Formation of an N-bromo amide intermediate: Deprotonation of amide Amide nitrogen anion as a nucleophile Ch.P396, ( 丙 ) Ch.P396, ( 丙 )

Step 2 Rearrangement of the N-bromo amide to an isocyanate （异氰酸酯） Deprotonation of N-bromo amide, the group R migrates from C atom to N atom to form an isocyanate. Step 3 Hydrolysis of isocyanate by base- catalyzed Carbamic acid ( 异氰酸 ) dissociates to an amine and CO 2

The features of Hofmann rearrangement: 1.N-unsubstituted amides as substrates 2. Rearrangement proceeds with retention of configuration at migrating group (S)-2-Methyl- 3-Phenylpropanamide (S)-1-Phenyl-2-propanamine

14. 7 Spectroscopic analysis of carboxylic acid derivatives Table 1. The stretching frequency of C=O IR: : The stretching frequency of : 2210~2260 cm -1 Compounds Stretching frequency of C=O (cm -1 ) RCOCl (RCO) 2 OR CO 2 R RCONH ~ ~1800 and 1780~ ~1630

Esters Carboxylic acid anhydrides Stretching frequency of C － O: 1310 ~1050 cm -1 Amides: Stretching frequency of N – H bond: 3500 ~3200 cm -1

α - H δ: 2 ~ 3 ppm 1 H NMR: 13 C NMR: δ: 120 ppm Amide: N - H δ: 5 ~8 ppm

Problems to chapter 14 P (a),(d),(e) 10.32(c)~(g) 10.33(b),(d),(g) (a),(c) (a), (c) (b) P (a),(d),(e) 10.32(c)~(g) 10.33(b),(d),(g) (a),(c) (a), (c) (b)