Hydrolysis of Amides Hydrolysis of Amides

Home , Acid hydrolysis

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 NH2 CH3 NH

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 R'

R O

R''

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 (CH2)16CH3

CH3(CH2)16 O O

(CH2)16CH3

Tristearin: found in many animal and vegetable fats Lactones are Cyclic Esters

O CH (CH ) CH O 2 2 6 3 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

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

RCOH + R'OH

H+

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

CH2OCCH3 + NaOH

CH 3 water-methanol, heat

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

CH3CH2COCH2CH3 + NaOH

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

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

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

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

RCOH + R'OH

HO–

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

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. The reaction that occurs is proton-transfer (acid-base). O O – + RCOH + R'NH2 RCO + R'NH3

If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating. Preparation of Amides

Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). O O – + RCOH + R'NH2 RCO + R'NH3 heat

RCNHR' + H2O Example

COH + H2N

225°C

CNH + H2O

(80-84%) 20.15 Lactams Lactams

Lactams are cyclic amides. Some are industrial chemicals, others occur naturally.

    -Caprolactam*: used to  N O prepare a type of nylon

*Caproic acid is the common name for hexanoic acid. Lactams

Lactams are cyclic amides. Some are industrial chemicals, others occur naturally.

C H CH CNH 6 5 2  S  CH3 N CH Highly 3 reactive O CO2H Penicillin G: a -lactam antibiotic 20.16 Imides Imides

Imides have 2 acyl groups attached to the nitrogen.

O O

RCNCR

R' Imides

The most common examples are cyclic imides.

O O

NH NH

O O

Succinimide Phthalimide Preparation of Imides

Cyclic imides are prepared by heating the ammonium salts of dicarboxylic acids. O O O O

NH3 – – HOCCH2CH2COH OCCH2CH2CO + +

O NH4 NH4

NH heat O 20.17 Hydrolysis of Amides Hydrolysis of Amides

Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. O O + + RCNHR' + H2O + H RCOH + R'NH3 Hydrolysis of Amides

In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion.

O O – – RCNHR' + HO RCO + R'NH2 Example: Acid Hydrolysis

O O

CH3CH 2CHCNH2 CH3CH2CHCOH

H O 2 + – + NH4 HSO4 H2SO4 heat (88-90%) Example: Basic Hydrolysis

CH 3CNH NH2 O KOH + CH3COK H2O heat Br Br (95%) Mechanism of Acid-Catalyzed Amide Hydrolysis

Acid-catalyzed amide hydrolysis proceeds via the customary two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate First stage: formation of tetrahedral intermediate

RCNH2 + H2O water adds to the carbonyl group of the H+ amide this stage is OH analogous to the acid- catalyzed addition of RC NH2 water to a ketone OH Second stage: cleavage of tetrahedral intermediate

O + RCOH + NH4

H+

RC NH2 OH Mechanism of formation of tetrahedral intermediate Step 1 H •• O• H O • + • RC H

• • NH2

H + •• O H • •O • RC H

• • NH2 Step 1 •• •O H RC

+ NH2 carbonyl oxygen is protonated because cation produced is stabilized by electron •• +O H delocalization (resonance) RC

• • NH2 Step 2 •• • • OH H + RC O •

• H •NH2

•• +O H H • • RC •O • • H • NH2 Step 3 •• • • OH H +

RC O • H • • • H •O • •NH2 H

•• • • OH H

RC O • H •• + • • H O • •NH2 H Cleavage of tetrahedral intermediate Step 4 •• • OH •• RC OH H •• • • + • O • H2N H H

•• • • OH H

RC O • •• H • H2N • H O • + • H Step 5 •• • OH •• RC OH •• + H N 2 H

•• • OH • RC + • NH3 + •• OH •• Step 6 •• • OH •• RC OH •• + H N 2 H + NH4

•• • OH + • H3O • RC + • NH3 + •• OH •• Step 6

•• •• + • OH OH RC RC + •• •• OH OH •• •• Step 6

H •• H O+

•• H O• H •• H O RC •• •• OH •• •• +O H

RC •• OH •• Mechanism of Amide Hydrolysis in Base

Involves two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate First stage: formation of tetrahedral intermediate

RCNH2 + H2O water adds to the carbonyl group of the – HO amide this stage is analogous to the OH base-catalyzed addition of water to a NH RC 2 ketone OH Second stage: cleavage of tetrahedral intermediate

O – RCO + NH3

HO–

RC NH2 OH Mechanism of formation of tetrahedral intermediate Step 1

•• O• • H • RC • O • •• – • • NH2

– •• • • • O • H

RC O • •• • •NH2 Step 2 •• • H O • H •• – • O• • • RC O • •• H • •NH2

•• – •• • O H • • • • O • H H RC O • •• • •NH2 Dissociation of tetrahedral intermediate Step 3 •• • OH •• RC OH H •• + • O • H N • •• • – 2 H

•• • • OH H

RC O • •• H • H2N • H O • •• • Step 4

•• H O • •• – • • •• • O• RC OH •• H + H3N

•• • •• • O H O • H RC

• • • O H •NH3 •• Step 5

•• O • RC – • O • ••

– •• HO O • RC

• • • O H •NH3 •• 20.18 Preparation of Nitriles Preparation of Nitriles

Nitriles are prepared by: nucleophilic substitution by cyanide on alkyl halides (Sections 8.1 and 8.13)

cyanohydrin formation (Section 17.7) dehydration of amides Example

KCN CH3(CH2)8CH2Cl CH3(CH2)8CH2C N ethanol- water (95%) SN2 Example

O OH KCN CH3CH2CCH2CH3 CH3CH2CCH2CH3 H+ C N

(75%) Preparation of Nitriles

By dehydration of amides uses the reagent P4O10 (often written as P2O5)

O P4O10 (CH3)2CHCNH2 (CH3)2CHC N 200°C (69-86%) 20.19 Hydrolysis of Nitriles Hydrolysis of Nitriles

O + + RCN + 2H2O + H RCOH + NH4

Hydrolysis of nitriles resembles the hydrolysis of amides. The reaction is irreversible. Ammonia is produced and is protonated to ammonium ion in acid solution. Hydrolysis of Nitriles

O – – + RCN + H2O + HO RCO NH3

In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. Example: Acid Hydrolysis

CH2CN CH2COH

H2O

H2SO4 heat

NO2 NO2 (92-95%) Example: Basic Hydrolysis

1. KOH, H2O, heat CH3(CH2)9CN CH3(CH2)9COH 2. H+ (80%) Mechanism of Hydrolysis of Nitriles

O O

H2O H2O RC N RCNH2 RCOH

Hydrolysis of nitriles proceeds via the corresponding amide. We already know the mechanism of amide hydrolysis. Therefore, all we need to do is to see how amides are formed from nitriles under the conditions of hydrolysis. Mechanism of Hydrolysis of Nitriles

OH O

H2O RC N RC NH RCNH2

The mechanism of amide formation is analogous to that of conversion of alkynes to ketones. It begins with the addition of water across the carbon-nitrogen triple bond. The product of this addition is the nitrogen analog of an enol. It is transformed to an amide under the reaction conditions. Step 1

H H – • • •O • • • •• • O•

RC N • RC • N • • – • Step 2

H • • O•

RC H

• H • N • H O • • – •• O• •• RC H

• • • N H • O • • – •• Step 3 H

• • O • H H • • O • •• – •• O•

H RC – O• • N H •• •• RC

• • N H Step 4

•• •• O• O•

RC RC – • N H • N H – •• •• •• • O • • H • • H O • H H 20.20 Addition of Grignard Reagents to Nitriles Addition of Grignard Reagents to Nitriles

NMgX NH R'MgX H O RC N RCR' 2 RCR' diethyl ether Grignard reagents add to carbon-nitrogen triple bonds in the same way that they add to carbon- oxygen double bonds. The product of the reaction is an imine. Addition of Grignard Reagents to Nitriles

NMgX NH R'MgX H O RC N RCR' 2 RCR' diethyl ether + H3O Imines are readily hydrolyzed to ketones. Therefore, the reaction of Grignard O reagents with nitriles can be used as a RCR' synthesis of ketones. Example

C N + CH3MgI

F3C 1. diethyl ether + 2. H3O , heat

CCH3 (79%)

F3C Information & Suggested Problems

Sample Available Posted on Website

------