CARBOXYLIC ACID DERIVATIVES CARBOXYLIC ACID An acyl group
CARBOXYLIC ACID DERIVATIVES
CARBOXYLIC ACID An acyl group
CARBOXYLIC ACID DERIVATIVES (Acyl derivatives) Carboxylic acid amide Carboxylic acid chloride Carboxylic acid anhydride Carboxylic acid ester Nitrile
Nucleophilic acyl substitution in carboxylic acid derivatives Net effect – replacing group Y with Nu Y is a leaving group: -Cl, -OR’, -NH 2, -NHR’, NR’ 2, -OCOR
Some nucleophilic acyl substitution reactions of carboxylic acids Carboxylic acid Acid chloride Amide Anhydride Ester
Reactivity of carboxylic acid derivatives in nucleophilic acyl substitution < < < Steric factors (substitution at α carbon) determine reactivity within a series of the same kind of acid derivatives Less reactive (sterically hindered) < REACTIVITY More reactive (sterically unhindered)
Reactivity of carboxylic acid derivatives Electronic factors (polarization of carbonyl group) determine reactivity of diferent acid derivatives < Amide Less reactive < Ester < < Acid anhydride REACTIVITY Acid chloride More reactive
Interconversions of carboxylic acid derivatives More reactive Acid chloride Acid anhydride Ester Less reactive Amide
General reactions of carboxylic acid derivatives (overview) H 2 O R’Mg. X Grignard reaction hydrolysis Acyl derivative R’OH alcoholysis [H] NH 3 aminolysis reduction
ACID HALIDES X = Cl or Br
Preparation 1. Reaction with thionyl chloride Oxalyl chloride (COCl)2 or phosphorus trichloride (PCl 3) can be used 2. Reaction with phosphorus tribromide
Examples: 90% yield 97% yield
Reactions of acid chlorides H 2 O R’Mg. X Ketone Acid chloride Acid R’Mg. X R’OH NH 3 [H] 3 Alcohol Ester [H] Amide Aldehyde 1 Alcohol
Hydrolysis: conversion of acid chlorides into acids Using of acid chlorides as acylating agents requires anhydrous conditions
Alcoholysis: conversion of acid chlorides into esters Excellent method for esters preparation Amine (pyridine) added for HCl scavenging
Examples: 97% yield 80% yield Pyridine is added for hydrogen chloride scavenging
Aminolysis: conversion of acid chlorides into amides Primary amide Secondary amide Tertiary amide Excellent method for amides preparation
Example: Schotten-Baumann reaction Sedative agent (an amide)
Reduction: conversion of acid chlorides into alcohols 96% yield Cannot be isolated
Reduction: conversion of acid chlorides into aldehydes 96% yield Li. Al. H(O-t-Bu)3 : lithium tri-tert-butoxyaluminum hydride, less powerful than Li. Al. H 4 reducing agent
Reaction of acid chlorides with Grignard reagents – tertiary alcohol formation Cannot be isolated 92% yield
Reaction of acid chlorides with Gilman reagents – ketone formation Lithium diorganocopper 92% yield Male ant hormone
ACID ANHYDRIDES
Preparation 1. Reaction between acid chloride and acid salt Both symmetrical and unsymmetrical anhydrides can be prepared 64% yield
Preparation 2. Dehydration of dicarboxylic acids – formation of cyclic anhydrides
2. Dehydration of dicarboxylic acids – formation of cyclic anhydrides
Reactions of acid anhydrides [H] H 2 O Acid anhydride Aldehyde R’OH Acid Ester NH 3 [H] Amide 1 Alcohol
Acetic anhydride is most frequently used for preparation of acetates of complex alcohols or substituted acetamides from amines. Examples: Component of anti headache drugs
ESTERS
Preparation 1. Reaction of carboxylic acid with alcohol (Fischer esterification) Limited to simple primary and secondary alcohols 2. Reaction of carboxylic acid salt with alkyl halide Limited to primary halides
Preparation 3. Reaction of carboxylic acid with diazomethane Limited to methyl esters 4. Reaction of acid chloride with alcohol Extremely general
Examples of esters synthesis: Pineapple aroma 97% yield Banana aroma
Examples of esters synthesis: 100% yield TOXIC AND EXPLOSIVE!
Esters in nature Plant oils and animal fats are esters of glycerol and carboxylic acids C 12 -C 22
Reactions of esters [H] Ester H 2 O Aldehyde NH 3 Acid + 2 R’’Mg. X [H] Alcohol Amide 3 Alcohol 1 Alcohol
Acid catalysed hydrolysis of esters (reversible)
Base catalysed hydrolysis of esters (irreversible)
Evidence supporting proposed mechanism
Aminolysis: conversion of esters into amides Method is not often used since higher yields are normally obtained by aminolysis of acid chlorides
Reduction: conversion of esters into alcohols 91% yield 86% yield
Reduction: conversion of esters into aldehydes 91% yield DIBAH = DIISOBUTYLALUMINUM HYDRIDE (i-Bu)2 Al. H
Reaction of esters with Grignard reagents – tertiary alcohol formation 96% yield
AMIDES Primary Secondary Tertiary
Preparation Primary amide Secondary amide Tertiary amide
Amides in nature Amide bonds
Reactions of amides Acidic hydrolysis H 2 O, HCl Amide [H] Basic hydrolysis H 2 O, Na. OH Amine
NITRILES
Preparation: 1. Substitution of bromine by cyanide Limited to primary halides
Preparation 2. Dehydration of primary amides Method of general utility. SOCl 2 (thionyl chloride) P 2 O 5 (phosphorus pentoxide) POCl 3 (phosphorus oxychloride) Ac 2 O (acetic anhydride) DEHYDRATING AGENTS
Similarity of nitriles to carbonyl compounds
Reactions of nitriles Amide R’Mg. X Nitrile H 2 O [H] Ketone H 2 O Acid Amine Aldehyde
Hydrolysis of nitriles Acid or base is necessary for hydrolysis. Elevated temperature is required. Amide intermediate sometimes can be isolated
Reduction of nitriles
Reaction with organomagnesium halides 89% yield
Biological Acetylation Reactions Acetylcoenzyme A (acetyl-Co. A) Biological acetylating reagent Acetyl
Acetylation of glucosylamine
α-Substitution of Carboxylic Acid Derivatives
Alkylation of ethyl acetoacetate RX RX, R’X
Monoalkylation of ethyl acetoacetate
Dialkylation of ethyl acetoacetate
Alkylation of diethyl malonate RX RX, R’X
Alkylation of diethyl malonate
Condensations of Carboxylic Acid Derivatives
Claisen condensation of ethyl acetate 75% yield
Mixed Claisen condensation of esters (β-ketoester)
Mixed Claisen condensation 91% yield
Intramolecular Claisen condensation
Perkin condensation
Biological Condensation Reactions
Biological Condensation Reactions: Fatty acids synthesis (lipogenesis)
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