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Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline I. DEFINITION & NOMENCLATURE OF CARBOXYLIC ACID DERIVATIVES A. CARBOXYLIC ACID DERIVATIVES The organic compounds that are classified as carboxylic acid derivatives are all carbonyl-containing compounds (except for nitriles) that can be converted to a carboxylic acid by hydrolysis, i.e., addition of water. This condition requires that the carboxylic acid derivative has an electronegative atom bonded to the carbon atom of the carbonyl group. The functional groups that belong to this class of compounds are: O O O R O R R" X Acyl halide Anhydride O O O R OR' (CH2)n Ester Lactone O O O O NH R NH2 R NHR' R NR'2 (CH2)n Primary Amide O R Secondary Amide O N H O R" Primary Imide R Tertiary Amide O O N R" H N Lactam O R' (CH2)n Secondary Imide Cyclic Imide (Primary) O R' N O (CH2)n Cyclic Imide (secondary) O R C Nitrile N H2N NH2 Urea B. NOMENCLATURE OF CARBOXYLIC ACID DERIVATIVES (21.1) 1. Nomenclature of Acyl Halides a. Acyl halides are named by replacing the "ic acid" ending of the corresponding carboxylic acid with "yl" followed by the halide. It is represented as two words. 2. Nomenclature of Anhydrides a. Symmetrical anhydrides (both carbonyl groups are the same) are named by replacing the "acid" suffix of the corresponding carboxylic acid with "anhydride" b. Unsymmetrical anhydrides are named by removing the "acid" suffix from each of the two acyl groups that make up the anhydride, placing the names in alphabetical order and adding an "anhydride" suffix. c. Cyclic anhydrides have common names. 3. Nomenclature of Esters a. Esters have two carbon containing components; one bonded to the oxygen atom ("alkyl") and one bonded to the carbonyl group ("alkanoate"). Esters are named by combining these two components. 4. Nomenclature of Amides a. Primary amides are named by replacing the "oic acid" or "ic acid" ending of the corresponding carboxylic acid with "amide". b. Secondary and tertiary amides are named as "N-alkyl-" or "N,N-dialkyl-" amides. The parent is determined as for primary amides. Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline II. PROPERTIES OF CARBOXYLIC ACID DERIVATIVES A Boiling points Carboxylic acid derivatives that cannot H-bond tend to have lower boiling points than those that can H-bond. Carboxylic acids and primary and secondary amides tend to have higher boiling points. B. Leaving groups The leaving groups associated with nucleophilic acyl addition reactions of carboxylic acid derivatives include: chlorides, carboxylate and carboxylic acids, alkoxides and alcohols, hydroxides and water, and amines. C. Primary imides are acidic O O O R N R R O N R H D. RELATIVE REACTIVITIES OF CARBOXYLIC DERIVATIVES WITH NUCLEOPHILES (21.2) Inductive and resonance effects help to predict the relative reactivity of carboxylic acids and derivatives. acyl halide O R ester acid anhydride O O > Cl O O ~ > R O amide O δ+ R carboxylic acid R very strong inductive effect due to electronegative Cl OR' > R OH R' NR2 inductive effect due to electronegative oxygen but less reactive than Cl O O δ+ R O R strong inductive effect enhanced by resonance effect IV. NUCLEOPHILIC ACYL SUBSTITUTIONS OF CARBOXYLIC ACIDS AND CARBOXYLIC ACID DERIVATIVES (21.2) A. MECHANISM OF THE NUCLEOPHILIC ACYL SUBSTITUTION REACTION Carboxylic acids and carboxylic acid derivatives react with nucleophiles via the nucleophilic acyl substitution reaction either under basic conditions or acidic conditions. Base-Catalyzed Nu Acyl Substitution O Nu Nu: R XR X = halogen, oxygen, nitrogen R O O XR R Nu Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline Acid-Catalyzed Nu Acyl Substitution H H H+ R O O O XR R R XR XR Nu X = halogen, oxygen, nitrogen H H O O O R R Nu H+ Nu: R Nu XR Nu H V. PREPARATION OF CARBOXYLIC ACID DERIVATIVES A. Preparation of Acyl halides 1. Acyl halides are usually prepared from carboxylic acids with SOCl2. B. Preparation of Anhydrides 1. Anhydrides are usually prepared by reacting acyl chlorides with carboxylic acids in the presence of pyridine. C. Preparation of Esters: Esters can be prepared in three ways. 1. Fisher Esterification: Reaction of alcohols with a carboxylic acid in the presence of an acid catalyst. 2. Reaction of alcohols with acyl chlorides in the presence of pyridine. 3. Reaction of alcohols with anhydrides in the presence of pyridine. D. Preparation of Amides 1. Primary amides are usually prepared by reaction of two moles of ammonia with acyl halides, anhydrides or esters. 2. Secondary and tertiary amides are usually prepared by reaction of two moles either a primary amine (to give a secondary amide) or a secondary amine (to give a tertiary amide) with acyl halides, anhydrides or esters. E. Preparation of Nitriles: Nitriles can be prepared in two ways. 1. Nucleophilic substitution of an alkyl halide 2. Nucleophilic addition of HCN with aldehydes & ketones VI. REACTIONS OF CARBOXYLIC ACID DERIVATIVES A. REACTIONS WITH ACYL HALIDES (Catalyst usually not needed) 1. Acyl halide reactions with oxygen nucleophiles (carboxylates, alcohols/phenols, water) to generate anhydrides, esters and carboxylic acids respectively. Reaction with a Carboxylate acyl halide O O R R O O Cl Cl O O R O O O R' anhydride product R carboxylate ion R Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline Reaction with an Alcohol acyl halide O O O R R Cl Cl R O O O H H ester product alcohol Reaction with a Phenol acyl halide O O O H R R Cl Cl R O O H O ester product phenol 2. Acyl halides react with primary and secondary amines to generate amides. acyl halide O O O H R R Cl Cl R N N NH H secondary amide H H primary amine B. REACTIONS OF ANHYDRIDES (Catalyst usually not needed) 1. Acid anhydride reactions with oxygen nucleophiles (alcohols/phenols, water) to generate esters and carboxylic acids Reaction with Alcohol acid anhydride O O O O R R O R' R O O O H alcohol O O 1 R O H + HO R' carboxylic acid ester product Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline Reaction with Phenol acid anhydride O O O O R R O R R' O R O + O H HO R' carboxylic acid ester product O phenol H 2. O O 1 Acid anhydrides react with primary and secondary amines to generate amides. Reaction with Primary Amine acid anhydride O O O O R R O R R' O H R N H N H O O 1 + N H amine C. Reactions of Esters 1. Ester reactions with oxygen nucleophiles (alcohols/phenols, water). Acid Catalyzed Reaction with Alcohols (Transesterification) ester H+ O R OH OR' R OH OR' R OH OR' OH OH R" R" R OR' OR" H+ H O O HOR' alcohol + R OR" new ester R R' carboxylic acid amide product H HO OR' OR" H Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline Acid Catalyzed Hydrolysis ester H+ O R OH OR' OH R OR' R OH OR' OH OH H H R OR' OH H+ H O O + HOR' alcohol R R OH OR' OH carboxylic acid H Base-Catalyzed Hydrolysis ester O O O H+ R R OR' OR' R OH R'OH alcohol RO' alkoxide carboxylic acid OH 2. + OH Ester reactions with primary and secondary amines to generate amides. Primary amines give secondary amides and secondary amines give tertiary amides. Reaction of Esters with Amines ester O O O R R OR" H R'N NHR' OR" H R NHR' amide + R'OH alcohol H 3. Ester reactions with carbon nucleophiles and hydrides. a. Esters react with Grignard reagents and primary or secondary alkyl lithiums to form alcohols i. Two equivalents of reagent is needed to convert esters to alcohols. Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline Reaction of Esters with Organometallic Reagents ester "intermediate ketone" O O O R R OR" H+ OR" CH3 R R"OH R"O + CH3 alcohol alkoxide CH3 CH3 (from Grignard or alkyl lithium) (second equivalent of reagent) O OH H+ R CH3 R CH3 CH3 CH3 Tertiary alcohol b. Esters are reduced with hydrides to alcohols with LiAlH4 to alcohols or to an alcohol and aldehyde with DIBAL i. Reaction with DIBAL gives an aldehyde and and alcohol. ii. If LiAlH4 is used as hydride reagent, the aldehyde continues to undergo reduction to a primary alcohol. Two alcohols (one primary, the other from the original ester) result as products of the reaction. Reaction of Esters with Hydrides aldehyde product if DIBAL ester O O O R R OR" H + R H R"OH R"O alcohol alkoxide H H DIBAL or LiAlH4 H+ OR" "intermediate aldehyde" if LiAlH4 (second equivalent of hydride if LiAlH4) O OH H+ R H H R H H Primary alcohol with LiAlH4 E. Reactions of Carboxylic Acids (Either activated or acid catalyzed) 1 Activation with SOCl2 Alcohols can be "activated" or converted to an acyl chloride with thionyl chloride prior to reaction with nucleophiles. Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline Reaction of Carboxylic Acid with Thionyl Chloride LG O O O O O S R R OH Cl O Cl S O R O Cl Cl Cl S Cl LG O O O S R R O Cl Cl Cl acid chloride 2. Reaction with alcohols (acid catalyzed) (Fisher esterification) Reaction of Carboxylic Acids with Alcohols (Acid-Catalyzed) H+ O R OH OH OH R OH R OH OH OH OR' R' H R OH OR' H+ alcohol H O O + H2O water R R OR' OH ester 3. OR' H Reaction with hydrides (1) LiAlH4 2) H+) Reaction of Carboxylic Acid with Hydride O O O R R H LiAlH4 OH H+ OH H + R H HO H 2O water hydroxide H "intermediate aldehyde" (second equivalent of hydride if LiAlH4) O OH H+ R H H R H H Primary alcohol with LiAlH4 Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline F. Reactions of Amides 1. Reaction with alcohols and water (acid- catalyzed) Reaction of Amides with Alcohols (Acid-Catalyzed) H+ O R OH NHR" R OH OH OH R NHR" OH OR' R' H R NHR" OR' H+ alcohol H O O + H2NR" R amine R OR' ester NHR" H OR' Acid-Catalyzed Hydrolysis of Amides H+ O R OH NHR" R OH OH OH R NHR" OH OH H H R NHR" OH H+ water H O O H2NR" amine + R R OH NHR" OH carboxylic acid H Base-Catalyzed Hydrolysis of Amides O O O R R NHR" OH 2. H+ NHR" OH R OH carboxylic acid + NHR" R"NH2 amine Reaction with hydrides i. LiAlH4 can be used to reduce amides to amines ii. Reduction of a primary amide gives a primary amines; reduction of a secondary amide gives a secondary amine and reduction of a tertiary amide gives a tertiary amine. Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions Lecture Outline Reaction of Amides with Hydrides "H+" O O OH R R NR" NHR" H R H NR" H H H LiAlH4 H-OH intermediate imine NR" R NR" H R NR" H R H H H H amine G. Hydrolysis of Imides and Nitriles 1. Hydrolysis of Imides: Gabriel Synthesis a. Imides can be used to synthesize amines through the Gabriel synthesis. b. The Gabriel synthesis is a multi-step reaction involving acid/base chemistry, an SN2 reaction followed by basecatalyzed hydrolysis to synthesize primary amines. Acid-Base Reaction O O (alkyl halide) OH R-X NH N O O phthalimide phthalimide ion O O OH OH SN2 Reaction NR NR O O N-substituted phthalimide Hydrolysis O OH OH OH NHR O O O OH NHR OH O OH O + H+ H2NR primary amine NHR Organic Chemistry Chapter 21: Carboxylic Acid Derivatives and Nu Acyl Substitutions 2. Lecture Outline Hydrolysis of Nitriles Nitriles can be hydrolyzed under acidic or basic conditions to provide primary amides. Acid-Catalyzed Hydrolysis of Nitriles H+ H+ N NH NH C NH H C C R C O R O R R H H OH H water NH2 NH2 C C R O O R H Primary amide Base-Catalyzed Hydrolysis of Nitriles H+ N NH N C R O H NH2 C C R NH O O H R O O R R H Primary amide