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Hydrolysis of Amides Hydrolysis of Amides Chem 234 Organic Chemistry II Professor Duncan J. Wardrop HO H H H N Cl NH S HN N N H OH O Cl Cl CO2H H N Cl H HO O O O N O O H H O CH3 O O NH H O MeO N O O O HO OMe O O OMe HO OMe N3 O CH H H2NSO2 3 N Br Br N H O N N CF3 Spring 2004 University of Illinois at Chicago 20.6 Reactions of Carboxylic Acid Anhydrides Reactions of Anhydrides O O RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Anhydrides Carboxylic acid anhydrides react with alcohols to give esters: O O O O R'OH R' R O R R O R OH normally, symmetrical anhydrides are used (both R groups the same) reaction can be carried out in presence of pyridine (a base) or it can be catalyzed by acids Reactions of Anhydrides Carboxylic acid anhydrides react with alcohols to give esters: O O O O RCOCR + R'OH RCOR' + RCOH H O R C OR' via: OCR O Reactions of Anhydrides- Examples O O CH3 OH CH3 O H2SO4 O CH3 CH CH CH 3 3 3 CH3 O (60%) Reactions of Anhydrides with Amines Acid anhydrides react with ammonia and amines to give amides: O O O O – RCOCR + 2R'2NH RCNR'2 + RCO H O + R'2NH2 R C NR' via: 2 OCR O Reactions of Anhydrides with Amines- Example O O NH2 CH3 NH CH3 O CH3 O CH3 CH3 CH3 CH3 (98%) Reactions of Anhydrides with Water Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): O O O RCOCR + H2O 2RCOH O O O – – RCOCR + 2HO 2RCO + H2O Reactions of Anhydrides with Water Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): O O O RCOCR + H2O 2RCOH H O R C OH OCR O Reactions of Anhydrides with Water - Example O O COH O + H2O COH O O 20.7 Sources of Esters Esters are Commonly Found in Natural Products O CH3 CH3 O CH3 3-methylbutyl acetate also called "isopentyl acetate" and "isoamyl acetate" contributes to characteristic odor of bananas Esters of Glycerol O O R' R O O O R'' O R, R', and R" can be the same or different called "triacylglycerols," "glyceryl triesters," or "triglycerides" fats and oils are mixtures of glyceryl triesters Fat & Oil are Mixtures of Glyceryl Triesters O O (CH2)16CH3 CH3(CH2)16 O O O (CH2)16CH3 O Tristearin: found in many animal and vegetable fats Lactones are Cyclic Esters O CH (CH ) CH O 2 2 6 3 H H (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) Preparation of Lactones 1. Fischer esterification (Sections 15.8 and 19.14) 2. from acyl chlorides (Sections 15.8 and 20.4) 3. from carboxylic acid anhydrides (Sections 15.8 and 20.6) 4. Baeyer-Villiger oxidation of ketones (Section 17.16) 20.9 Reactions of Esters: A Review and a Preview Reactions of Esters 1. with Grignard reagents (Section 14.10) 2. reduction with LiAlH4 (Section 15.3) 3. with ammonia and amines (Sections 20.12) 4. hydrolysis (Sections 20.10 and 20.11) 20.10 Acid-Catalyzed Ester Hydrolysis Acid-Catalyzed Hydrolysis of Esters Mechanism is just the reverse of Fischer esterification O O R' H2O H OH R O R O R' maximize conversion to ester by removing water maximize ester hydrolysis by having large excess of water equilibrium is closely balanced because carbonyl group of ester and of carboxylic acid are comparably stabilized Acid-Catalyzed Hydrolysis of Esters - Example ADD WATER Cl Cl OH O CH3 HCl O O Heat CH3 OH REMOVE WATER Acid-Catalyzed Hydrolysis of Esters - Mechanism Is the reverse of the mechanism for acid- catalyzed esterification. Like the mechanism of esterification, it involves two stages: 1) formation of tetrahedral intermediate (3 steps) 2) dissociation of tetrahedral intermediate (3 steps) First stage: formation of tetrahedral intermediate O RCOR' + H2O water adds to the carbonyl group of the H+ ester this stage is OH analogous to the acid- catalyzed addition of RC OR' water to a ketone OH Second stage: cleavage of tetrahedral intermediate O RCOH + R'OH H+ OH RC OR' OH Mechanism of formation of tetrahedral intermediate Step 1 H •• O• H O • + • RC H • O R' •• H + •• O H • •O • RC H • O R' •• Step 1 •• •O H RC + O R' •• carbonyl oxygen is protonated because cation produced is stabilized by electron •• +O H delocalization (resonance) RC • O R' •• Step 2 •• • • OH H + RC O • H •OR' •• •• +O H H • • RC •O • H • O R' •• Step 3 •• • • OH H + RC O • H • • H •O • •OR' •• H •• • OH H RC O • H •• + • H O • •OR' •• H Cleavage of tetrahedral intermediate Step 4 •• • OH •• RC OH H •• + • O • O • • R' •• H H •• • OH •• RC OH •• H O • H O • R' •• + • H Step 5 •• • OH •• RC OH •• + O R' •• H •• • OH •• RC + O + •• R' •• H OH •• Step 5 •• •• + • OH OH RC RC + •• •• OH OH •• •• Step 6 H •• H O+ •• H O• H •• H O RC •• •• OH •• •• +O H RC •• OH •• Key Features of Acid-Catalyzed Hydrolysis 1. Activation of carbonyl group by protonation of carbonyl oxygen 2. Nucleophilic addition of water to carbonyl group forms tetrahedral intermediate 3. Elimination of alcohol from tetrahedral intermediate restores carbonyl group Investigation of Mechanism via 18O Labeling Studies O COCH2CH3 + H2O 1. Ethyl benzoate, labeled with 18O at the carbonyl oxygen, was subjected to acid-catalyzed hydrolysis. H+ 2. Ethyl benzoate, recovered before the reaction had gone to completion, had lost its 18O label. 3. This observation is consistent with a tetrahedral intermediate. O + COCH2CH3 H2O Investigation of Mechanism via 18O Labeling Studies O COCH2CH3 + H2O H+ OH C OCH2CH3 H+ OH O + COCH2CH3 H2O 20.11 Ester Hydrolysis in Base: Saponification Ester Hydrolysis in Aqueous Base O O Irreversible R' HO- OH R O R O- R' 1. is called saponification 2. is irreversible, because of strong stabilization of carboxylate ion 3. if carboxylic acid is desired product, saponification is followed by a separate acidification step (simply a pH adjustment) Ester Hydrolysis in Aqueous Base - Example 1 O CH2OCCH3 + NaOH CH 3 water-methanol, heat O CH2OH + CH3CONa CH (95-97%) 3 Ester Hydrolysis in Aqueous Base - Example 2 O O 1. NaOH, H2O CH CH 3 3 heat CH O 3 OH CH3OH 2. H2SO4 Manufacture of Soap O Basic hydrolysis O (CH2)yCH3 of the glyceryl CH3(CH2)x O triesters (from O fats and oils) O gives salts of (CH2)zCH3 long-chain O carboxylic acids. These salts are K CO , H O, heat soaps. 2 3 2 O O O CH3(CH2)xCOK CH3(CH2)yCOK CH3(CH2)zCOK Is the Mechanism BAL2 or BAC2? •• •• • • •O •O – – •• •• •• ••• RCO R' + • OH RCO• + R'OH •• • •• •• •• One possibility is an SN2 attack by hydroxide on the alkyl group of the ester. Carboxylate is the leaving group. This mechaism would be designated BAL2: B (Basic conditions) AL (Carbonyl-OAlkyl bond breaking in rate-determining step) 2 (Reaction is second order - rate = k[ester][hydroxide] Is the Mechanism BAL2 or BAC2? •• •• •O • • •O •• – •• – •• + • •• RC OR' • OH RC OH + •OR' •• •• •• •• A second possibility is nucleophilic acyl substitution. 18O Labeling gives the answer O CH3CH2COCH2CH3 + NaOH O CH3CH2CONa + CH3CH2OH 18O retained in alcohol, not carboxylate; therefore nucleophilic acyl substitution. Stereochemistry gives the same answer H O alcohol has same C6H5 configuration at CH3C O C chirality center as ester; therefore, CH3 nucleophilic acyl KOH, H2O substitution H O not S 2 C6H5 N CH3COK + HO C CH3 Does it proceed via a tetrahedral intermediate? •• •• •O • • •O •• – •• – •• + • •• RC OR' • OH RC OH + •OR' •• •• •• •• Does nucleophilic acyl substitution proceed in a single step, or is a tetrahedral intermediate involved? 18O Labeling Studies O COCH2CH3 + H2O Ethyl benzoate, labeled with 18O at the carbonyl oxygen, was subjected to hydrolysis in base. Ethyl benzoate, recovered before the reaction had gone HO– to completion, had lost its 18O label. This observation is consistent with a tetrahedral intermediate. O + COCH2CH3 H2O 18O Labeling Studies O COCH2CH3 + H2O HO– OH C OCH2CH3 HO– OH O + COCH2CH3 H2O Mechanism of Ester Hydrolysis in Base Involves two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate First stage: formation of tetrahedral intermediate O RCOR' + H2O water adds to the carbonyl group of the HO– ester this stage is analogous to the OH base-catalyzed addition of water to a OR' RC ketone OH Second stage: cleavage of tetrahedral intermediate O RCOH + R'OH HO– OH RC OR' OH Mechanism of formation of tetrahedral intermediate Step 1 •• O• • H • RC • O • •• – • OR' •• – •• • • • O • H RC O • •• •OR' •• Step 2 •• • H O • H •• – • O• • • RC O • •• H •OR' •• •• – •• • O H • • • • O • H H RC O • •• •OR' •• Dissociation of tetrahedral intermediate Step 3 •• • H O • H •• – • O• • • RC O • •• H •OR' •• •• • •• • O H O • H RC – •• • • O H •OR' •• •• Step 4 •• O • RC – • O • •• •• H OR' – •• •• HO O • RC H2O – •• • • O H •OR' •• •• Key Features of Mechanism Nucleophilic addition of hydroxide ion to carbonyl group in first step Tetrahedral intermediate formed in first stage Hydroxide-induced dissociation of tetrahedral intermediate in second stage 20.11 Reactions of Esters with Ammonia and Amines Reactions of Esters O RCOR' O RCNR'2 O RCO– Reactions of Esters Esters react with ammonia and amines to give amides: O O RCOR' + R'2NH RCNR'2 + R'OH H O via: R C NR'2 OR' Example O + H2C CCOCH3 NH3 CH3 H2O O + H2C CCNH2 CH3OH (75%) CH3 Example O FCH COCH CH + 2 2 3 NH2 heat O FCH2CNH + CH3CH2OH (61%) 20.14 Preparation of Amides Preparation of Amides Amides are prepared from amines by acylation with: acyl chlorides (Table 20.1) anhydrides (Table 20.2) esters (Table 20.5) Preparation of Amides Amines do not react with carboxylic acids to give amides.
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