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