20.13 Hydrolysis of Amides Dr. Wolf's CHM 201 & 202 10

Hydrolysis of Amides Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. RCNHR' O RCOH O + + + H2O + H + R'NH3 Dr. Wolf's CHM 201 & 202 5

In basic solution the carboxylic acid product Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. RCNHR' O RCO O – – + HO + R'NH2 Dr. Wolf's CHM 201 & 202 5

Example: Acid Hydrolysis CH3CH2CHCNH2 O CH3CH2CHCOH O H2O NH4 + HSO4 – + H2SO4 heat (88-90%) Dr. Wolf's CHM 201 & 202 4

Example: Basic Hydrolysis CH3CNH O Br NH2 Br CH3COK O KOH + H2O heat (95%) Dr. Wolf's CHM 201 & 202 4

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 Dr. Wolf's CHM 201 & 202 5

First stage: formation of tetrahedral intermediate + H2O RCNH2 O water adds to the carbonyl group of the amide this stage is analogous to the acid-catalyzed addition of water to a ketone H+ RC OH NH2 Dr. Wolf's CHM 201 & 202 5

Second stage: cleavage of tetrahedral intermediate RCOH O NH4 + + H+ RC OH NH2 Dr. Wolf's CHM 201 & 202 5

Mechanism of formation of tetrahedral intermediate Dr. Wolf's CHM 201 & 202 8

Step 1 O + H RC O NH2 RC O NH2 + H •• • • • • •• • • 8 Dr. Wolf's CHM 201 & 202 8

Step 1 RC O NH2 •• • • + H carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) RC O NH2 •• • • + H Dr. Wolf's CHM 201 & 202 8

Step 2 RC OH NH2 O + H RC O NH2 + H O H •• • • •• • • • • 8 Dr. Wolf's CHM 201 & 202 8

Step 3 RC OH NH2 O + H O H O H + NH2 RC OH •• • • • • •• • • 8 Dr. Wolf's CHM 201 & 202 8

Cleavage of tetrahedral intermediate Dr. Wolf's CHM 201 & 202 8

Step 4 O H RC OH H2N + H2N RC OH O H O H + •• • • •• • • • • 8 Dr. Wolf's CHM 201 & 202 8

Step 5 OH RC + H2N H OH + NH3 RC •• • • •• • • 8 Dr. Wolf's CHM 201 & 202 8

Step 6 OH RC + H2N H + NH4 + OH H3O + NH3 RC + •• • • •• • • • • 8 Dr. Wolf's CHM 201 & 202 8

Step 6 RC OH •• + RC OH •• • • + Dr. Wolf's CHM 201 & 202 8

Step 6 H O + H O RC OH + O H RC OH •• • • •• •• •• 8 Dr. Wolf's CHM 201 & 202 8

Mechanism of Amide Hydrolysis in Base Involves two stages: 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate Dr. Wolf's CHM 201 & 202 5

First stage: formation of tetrahedral intermediate + H2O RCNH2 O water adds to the carbonyl group of the amide this stage is analogous to the base-catalyzed addition of water to a ketone HO– RC OH NH2 Dr. Wolf's CHM 201 & 202 5

Second stage: cleavage of tetrahedral intermediate RCO O – + NH3 HO– RC OH NH2 Dr. Wolf's CHM 201 & 202 5

Mechanism of formation of tetrahedral intermediate Dr. Wolf's CHM 201 & 202 8

Step 1 O H RC O – NH2 – O H RC NH2 •• • • • • •• •• • • 8 Dr. Wolf's CHM 201 & 202 8

Step 2 RC O NH2 H – RC O NH2 H – H O •• • • •• •• • • • • 8 Dr. Wolf's CHM 201 & 202 8

Dissociation of tetrahedral intermediate Dr. Wolf's CHM 201 & 202 8

Step 3 RC OH H2N H + O – H2N RC OH O H O H •• • • •• • • • • •• 8 Dr. Wolf's CHM 201 & 202 8

Step 4 H O – O H RC OH + H3N H O NH3 RC •• • • •• •• • • •• •• • • 8 Dr. Wolf's CHM 201 & 202 8

Step 5 O RC – HO– O RC H NH3 •• • • •• • • • • 8 Dr. Wolf's CHM 201 & 202 8

20.14 Lactams Dr. Wolf's CHM 201 & 202 1

-Caprolactam*: used to prepare a type of nylon    Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. N H O -Caprolactam*: used to prepare a type of nylon      *Caproic acid is the common name for hexanoic acid. Dr. Wolf's CHM 201 & 202 5

Penicillin G: a -lactam antibiotic Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. Penicillin G: a -lactam antibiotic   CH3 S CO2H O N C6H5CH2CNH Dr. Wolf's CHM 201 & 202 5

20.15 Preparation of Nitriles Dr. Wolf's CHM 201 & 202 1

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 Dr. Wolf's CHM 201 & 202 5

Example KCN CH3(CH2)8CH2Cl CH3(CH2)8CH2C N (95%) SN2 ethanol- water 4 Dr. Wolf's CHM 201 & 202 4

Example CH3CH2CCH2CH3 O CH3CH2CCH2CH3 OH C N KCN H+ (75%) 4 Dr. Wolf's CHM 201 & 202 4

Preparation of Nitriles By dehydration of amides uses the reagent P4O10 (often written as P2O5) (CH3)2CHCNH2 O P4O10 200°C (CH3)2CHC N (69-86%) Dr. Wolf's CHM 201 & 202 5

20.16 Hydrolysis of Nitriles Dr. Wolf's CHM 201 & 202 1

Hydrolysis of Nitriles + NH4 RCOH O RCN 2H2O H Hydrolysis of nitriles resembles the hydrolysis of amides. The reaction is irreversible. Ammonia is produced and is protonated to ammonium ion in acid solution. Dr. Wolf's CHM 201 & 202 5

Hydrolysis of Nitriles + – RCO O HO NH3 RCN H2O In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. Dr. Wolf's CHM 201 & 202 5

Example: Acid Hydrolysis H2O H2SO4 heat CH2CN NO2 CH2COH (92-95%) Dr. Wolf's CHM 201 & 202 4

Example: Basic Hydrolysis CH3(CH2)9COH O 1. KOH, H2O, heat 2. H+ CH3(CH2)9CN (80%) Dr. Wolf's CHM 201 & 202 4

Mechanism of Hydrolysis of Nitriles RCNH2 O RCOH O H2O H2O RC N 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. Dr. Wolf's CHM 201 & 202 5

Mechanism of Hydrolysis of Nitriles OH RCNH2 O H2O RC N RC NH 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. Dr. Wolf's CHM 201 & 202 5

Step 1 O • • H •• – RC O N • • – H RC N • • Dr. Wolf's CHM 201 & 202 8

Step 2 H O RC N H O – RC H N O – • • • • •• • • •• 8 Dr. Wolf's CHM 201 & 202 8

Step 3 – RC O N H – O H RC O N H •• • • •• • • • • •• 8 Dr. Wolf's CHM 201 & 202 8

Step 4 N RC O H – – RC O N H O H •• • • •• • • • • •• 8 Dr. Wolf's CHM 201 & 202 8

20.17 Addition of Grignard Reagents to Nitriles Dr. Wolf's CHM 201 & 202 1

Addition of Grignard Reagents to Nitriles RCR' NMgX RCR' NH R'MgX H2O RC N 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. Dr. Wolf's CHM 201 & 202 5

Addition of Grignard Reagents to Nitriles RCR' NMgX RCR' NH R'MgX H2O RC N diethyl ether H3O+ Imines are readily hydrolyzed to ketones. Therefore, the reaction of Grignard reagents with nitriles can be used as a synthesis of ketones. RCR' O Dr. Wolf's CHM 201 & 202 5

Example F3C C N + CH3MgI 1. diethyl ether 2. H3O+, heat F3C CCH3 O (79%) Dr. Wolf's CHM 201 & 202 4

Section 20.18 Spectroscopic Analysis of Carboxylic Acid Derivatives Dr. Wolf's CHM 201 & 202 1

Infrared Spectroscopy C=O stretching frequency depends on whether the compound is an acyl chloride, anhydride, ester, or amide. 1822 cm-1 1748 and 1815 cm-1 1736 cm-1 1694 cm-1 C=O stretching frequency  CH3CCl O CH3COCCH3 O CH3COCH3 O CH3CNH2 O Dr. Wolf's CHM 201 & 202 6

Infrared Spectroscopy Anhydrides have two peaks due to C=O stretching. One results from symmetrical stretching of the C=O unit, the other from an antisymmetrical stretch. C=O stretching frequency  CH3COCCH3 O 1748 and 1815 cm-1 Dr. Wolf's CHM 201 & 202 6

Infrared Spectroscopy Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching in the 2210- 2260 cm-1 region. Dr. Wolf's CHM 201 & 202 6

1H NMR RCOR' O R'COR O and O C H is less shielded than 1H NMR readily distinguishes between isomeric esters of the type: RCOR' O R'COR O and O C H is less shielded than Dr. Wolf's CHM 201 & 202 6

1H NMR For example: CH3COCH2CH3 O O and CH3CH2COCH3 Both have a triplet-quartet pattern for an ethyl group and a methyl singlet. They can be identified, however, on the basis of chemical shifts. Dr. Wolf's CHM 201 & 202 6

O O CH3CH2COCH3 CH3COCH2CH3 1 Figure 20.9 Chemical shift (, ppm) 1.0 1.0 2.0 3.0 4.0 5.0 CH3CH2COCH3 O CH3COCH2CH3 O Figure 20.9 1.0 2.0 3.0 4.0 5.0 Dr. Wolf's CHM 201 & 202 Chemical shift (, ppm) 1

The carbon of a CN group appears near  120 ppm. 13C NMR Carbonyl carbon is at low field ( 160-180 ppm), but not as deshielded as the carbonyl carbon of an aldehyde or ketone ( 190-215 ppm). The carbon of a CN group appears near  120 ppm. Dr. Wolf's CHM 201 & 202

UV-VIS n* absorption: max CH3CCl O CH3COCCH3 O CH3COCH3 O CH3CNH2 O Dr. Wolf's CHM 201 & 202 6

Mass Spectrometry Most carboxylic acid derivatives give a prominent peak for an acylium ion derived by the fragmentation shown. RCX •• O • • RCX •+ O • • RC O + • • + • • • X Dr. Wolf's CHM 201 & 202

Mass Spectrometry Amides, however, cleave in the direction that gives a nitrogen-stabilized cation. RCNR'2 •• O • • •+ RCNR'2 O • • •• + O C • • NR'2 •• • R + Dr. Wolf's CHM 201 & 202

End of Chapter 20 Dr. Wolf's CHM 201 & 202