Lecture 19 Nucleophilic Acyl Substitution •• - • O• •• •• • R • O• Y- O• - C X + X C C R X R Y Y April 2, 2019 Chemistry 328N Acid-catalyzed Esterification (also called Fischer esterification) O O H+ COH+ CH3OH COCH3+ H2O Please study the mechanism Chemistry 328N Decarboxylation of b-keto acids H H O O O O O C C C C R-CH -C-OH + CO2 R C O R C O 2 H H H H enol of a carboxylic acid Please study the mechanism too Chemistry 328N Practice Heat Chemistry 328N Practice these at home O O O Chemistry 328N Acid Chlorides ⚫ The functional group is a carbonyl bonded to a chlorine atom ⚫ Name derived from the parent acid by dropping –ic acid and adding yl chloride O O O -C-X CH3 CCl CCl Functional group Acetyl chloride Benzoyl chloride of an acid halide Chemistry 328N Acid Chlorides ⚫ Acid chlorides are most often prepared by treatment of a carboxylic acid with thionyl chloride - SOCl2 O O CH CH CH COH + SOCl 3 2 2 2 CH3 CH2 CH2 CCl + SO2 + HCl Butanoic acid Thionyl Butanoyl chloride chloride Chemistry 328N Acid Chlorides ⚫ The mechanism divided into two steps. Step 1: The -OH, is transformed into a chlorosulfite group, a great leaving group O O O O R-C-OH + Cl-S-Cl R C O S Cl + HCl A chlorosulfite group Chemistry 328N Acid Chlorides Step 2: attack of chloride ion gives a tetrahedral carbonyl addition intermediate, which collapses to give the acid chloride - O O O O O - - R C O S Cl + Cl R C O S Cl R-C-Cl + SO2 + Cl Cl A tetrahedral carbonyl addition intermediate Chemistry 328N Nucleophilic Acyl Substitution with an anion as nucleophile •• - • O• •• •• • R • O• Y- O• - C X + X C C R X R Y Y This is a very IMPORTANT general reaction. Understanding the mechanism allows one to explain and predict a large body of organic chemistry! Chemistry 328N The best leaving group wins ⚫ What makes a leaving group “good” – Stablility of the anion – The conjugate bases of strong acids are greatleaving groups. Chemistry 328N Reactions of Acyl Chlorides O RCCl O O RCOCR' O RCOR' O RCNR'2 O RCO– Chemistry 328N Chemistry 328N Reactions of Acyl Chlorides Acyl chlorides react with carboxylic acids to give acid anhydrides: O O O O RCCl + R'COH RCOCR' + HCl H O O via: R C OCR' Cl Chemistry 328N Acid Anhydrides ⚫ The functional group of an acid anhydride is two acyl groups bonded to an oxygen atom – the anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups) ⚫ To name, replace acid of the parent acid by anhydride O O O O O O CH3 COCCH3 COC CH3 COC- Acetic anhydride Benzoic anhydride Acetic benzoic anhydride Chemistry 328N Reactions of Acyl Chlorides Acyl chlorides react with alcohols to give esters: O O RCCl + R'OH RCOR' + HCl Please review the nomenclature of esters Chemistry 328N Reactions of Acyl Chlorides Acyl chlorides react with water (or base) to give carboxylic acids (carboxylate ion in base): Hydrolysis O O RCCl + H2O RCOH + HCl O O – – – RCCl + 2HO RCO + Cl + H2O Chemistry 328N Reactivity ⚫ Acyl chlorides undergo nucleophilic acyl substitution much faster than the corresponding alkyl chlorides. O C6H5CCl C6H5CH2Cl Relative rates of 1,000 1 hydrolysis (25°C) Chemistry 328N Reactions of Acyl Chlorides Acyl chlorides react with ammonia and amines to give amides: O O + – RCCl R'2NH RCNR'2 + Cl O via: R C NR'2 Cl Chemistry 328N Example O O CH3(CH2)5CCl + CH3(CH2)5COH pyridine O O CH3(CH2)5COC(CH2)5CH3 Chemistry 328N Example of acyl chloride reaction with amines to make amides O O NaOH C6H5CCl + HN C6H5CN H2O Chemistry 328N Amides ⚫ The functional group of an amide is an acyl group bonded to a nitrogen atom ⚫ IUPAC: drop -oic acid from the name of the parent acid and add -amide ⚫ If the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by N- O O O CH3 CNH2 CNH2 CH3 CNHCH3 Acetamide Benzamide N-Methylacetamide (a 1° amide) (a 1° amide) (a 2° amide) Chemistry 328N Amides ⚫ Cyclic amides are called lactams ⚫ Name the parent carboxylic acid, drop the suffix -ic acid, and add -lactam O b 2 O 3 1 2 1 3 4 NH b NH 5 6 H3 C 3-Butanolactam 6-Hexanolactam (b-Butyrolactam) (-Caprolactam) Chemistry 328N Lactam Antibiotics Chemistry 328N Reactions of Acid Anhydrides ⚫ Acid anhydrides react with alcohols to give one mol of ester and one of carboxylic acid O CH O 3 CH 3 COCHCH 2 CH3 + O HOCHCH 2 CH3 COH O O Phthalic 2-Butanol sec-Butyl hydrogen anhydride (sec-Butyl alcohol) phthalate Chemistry 328N Reactions of Esters • Esters react with ammonia and amines to give amides: O O + RCOR R'2NH RCNR'2 + ROH H O via: R C NR'2 OR Chemistry 328N Reaction of Esters with Grignard Reagents O O H O + 2 - + RCOCH3 NaOH RCO Na + CH3 OH Chemistry 328N Reaction of Esters with OH - ⚫ Saponification O O H O + 2 - + RCOCH3 NaOH RCO Na + CH3 OH Chemistry 328N Saponification of Esters ⚫ Hydrolysis of an esters is aqueous base is called saponification ⚫ Each mol of ester hydrolyzed requires 1 mol of base; for this reason, ester hydrolysis in aqueous base is said to be “base-promoted” (not catalyzed) O O H O + 2 - + RCOCH3 NaOH RCO Na + CH3 OH ⚫ Hydrolysis of an ester in aqueous base involves Nucleophilic acyl substitution Chemistry 328N Saponification of Fat O CH2 OH O O CH2 O C R NaOH R C O C H H C OH C - + R O Na CH OH CH2 O C R 2 O Fat glycerol Fatty Acid Salt "Soap" R = CH3(CH2)16COOH Stearic Acid CH3(CH2)7CH CH(CH2)7COOH Oleic acid etc. Chemistry 328N Physical Properties ⚫ Water solubility decreases as the relative size of the hydrophobic portion of the molecule increases hydrophilic region; increases water solubility hydrophobic region; decreases water solubility Chemistry 328N Soaps and Detergents Surface Active Agents = surfactants - + CH3(CH2)16 COO Na Soap O + CH3(CH2)11 S O'Na Anionic detergent O CH3 Cl Cationic Detergent CH2 N (CH2)15CH3 CH3 Chemistry 328N Chemistry 328N Chemistry 328N Hydrolysis of Amides Hydrolysis of amides is also irreversible. In acid solution the amine product is protonated to give an ammonium salt. O O + + RCNHR' + H2O + H RCOH + R'NH3 Chemistry 328N Hydrolysis of Amides • In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. • This makes the reaction irreversible! O O – – RCNHR' + HO RCO + R'NH2 Chemistry 328N Hydrolysis of Amides in Acid ⚫ Hydrolysis of amides in aqueous acid requires 1 mol of acid per mol of amide O H2 O CH CH CHCNH + H O + HCl 3 2 2 2 heat Ph 2-Phenylbutanamide O + - CH3 CH2 CHCOH + NH4 Cl Ph 2-Phenylbutanoic acid Chemistry 328N Hydrolysis of Amides in Acid ⚫ Acid-catalyzed hydrolysis of an amide is divided into three steps Step 1: protonation of the carbonyl oxygen •• •• O + + •• •• •• •• •• OH OH R C NH + H O H + 2 •• •• •• R C NH R C NH + H O H 2 2 2 Resonance-stabilized cation Chemistry 328N Hydrolysis of Amides in Acid Step 2: addition of H2O to the carbonyl carbon followed by proton transfer •• •• •• •• •• •• OH OH proton transfer OH + •• •• •• from O to N + R C NH2 + O H R C NH2 R C NH3 + •• H O OH H •• H •• Tetrahedral carbonyl addition intermediate Chemistry 328N Hydrolysis of Amides in Acid Step 3: collapse of the intermediate coupled with proton transfer to give the carboxylic acid and ammonium ion + OH O H O + R C NH + 3 R C NH3 + + R C OH NH4 OH OH Chemistry 328N Hydrolysis of Amides in Base ⚫ Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide O O H2 O - + CH3 CNH + NaOH + H N heat CH3 CO Na 2 N-Phenylethanamide Sodium acetate Aniline Chemistry 328N Hydrolysis of Amides in Base ⚫ Hydrolysis of an amide in aqueous base is divided into three steps Step 1: addition of hydroxide ion to the carbonyl carbon - O O - R C NH2 + OH R C NH2 OH Tetrahedral carbonyl addition intermediate Chemistry 328N Hydrolysis of Amides in Base Step 2: collapse of the intermediate to form a carboxylic acid and ammonia •• •• •• •• •• - O O •• •• •• - •• •• R C NH + H O H R C + NH + OH 2 •• 3 •• •• •• OH OH •• •• Tetrahedral carbonyl addition intermediate A very rare event… Why??? Chemistry 328N Hydrolysis of Amides in Base Step 3: proton transfer to form the carboxylate anion and water. Hydrolysis is driven to completion by this acid-base reaction •• •• •• •• O O •• •• -•• •• •• - •• R C O H + O-H R C O + H O H •• •• •• •• Chemistry 328N.