1. 20.13 Hydrolysis of Amides
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2. 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
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3. 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
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4. Example: Acid Hydrolysis
CH3CH2CHCNH2 O
CH3CH2CHCOH O
H2O
NH4 +
HSO4 – +
H2SO4 heat
(88-90%)
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5. Example: Basic Hydrolysis
CH3CNH O Br
NH2 Br
CH3COK O
KOH +
H2O heat
(95%)
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6. 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
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7. 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
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8. Second stage: cleavage of tetrahedral intermediate
RCOH O
NH4 + + H+ RC OH
NH2
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9. Mechanism of formation of tetrahedral intermediate
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10. Step 1 O + H RC O NH2 RC O NH2 + H •• • • • • •• • • 8
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11. Step 1 RC O
NH2 ••
• • + H
carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) RC O
NH2 ••
• • + H
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12. Step 2 RC OH NH2 O + H RC O NH2 + H O H •• • • •• • • • • 8
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13. Step 3 RC OH NH2 O + H O H O H + NH2 RC OH •• • • • • •• • • 8
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14. Cleavage of tetrahedral intermediate
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15. Step 4 O H RC OH H2N + H2N RC OH O H O H + •• • • •• • • • • 8
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16. Step 5 OH RC + H2N H OH + NH3 RC •• • • •• • • 8
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17. Step 6 OH RC + H2N H + NH4 + OH H3O + NH3 RC + •• • • •• • • • • 8
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18. Step 6 RC OH •• + RC OH ••
• • +
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19. Step 6 H O + H O RC OH + O H RC OH •• • • •• •• •• 8
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20. Mechanism of Amide Hydrolysis in Base
Involves two stages:
1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate
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21. 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
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22. Second stage: cleavage of tetrahedral intermediate
RCO O – +
NH3
HO– RC OH
NH2
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23. Mechanism of formation of tetrahedral intermediate
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24. Step 1 O H RC O – NH2 – O H RC NH2 •• • • • • •• •• • • 8
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25. Step 2 RC O NH2 H – RC O NH2 H – H O •• • • •• •• • • • • 8
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26. Dissociation of tetrahedral intermediate
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27. Step 3 RC OH H2N H + O – H2N RC OH O H O H •• • • •• • • • • •• 8
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28. Step 4 H O – O H RC OH + H3N H O NH3 RC •• • • •• •• • • •• •• • • 8
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29. Step 5 O RC – HO– O RC H NH3 •• • • •• • • • • 8
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30. 20.14 Lactams
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31. -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.
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32. 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
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33. 20.15 Preparation of Nitriles
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34. 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
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35. Example KCN CH3(CH2)8CH2Cl CH3(CH2)8CH2C N (95%) SN2 ethanol- water 4
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36. Example CH3CH2CCH2CH3 O CH3CH2CCH2CH3 OH C N KCN H+ (75%) 4
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37. 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%)
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38. 20.16 Hydrolysis of Nitriles
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39. 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.
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40. Hydrolysis of Nitriles+ –
RCO O HO
NH3
RCN
H2O
In basic solution the carboxylic acid product
is deprotonated to give a carboxylate ion.
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41. Example: Acid Hydrolysis
H2O
H2SO4 heat
CH2CN
NO2
CH2COH
(92-95%)
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42. Example: Basic Hydrolysis
CH3(CH2)9COH O
1. KOH, H2O, heat
2. H+
CH3(CH2)9CN
(80%)
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43. 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.
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44. Mechanism of Hydrolysis of NitrilesOH
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.
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45. Step 1 O
• • H •• – RC O N
• • – H RC N
• •
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46. Step 2 H O RC N H O – RC H N O – • • • • •• • • •• 8
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47. Step 3 – RC O N H – O H RC O N H •• • • •• • • • • •• 8
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48. Step 4 N RC O H – – RC O N H O H •• • • •• • • • • •• 8
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49. 20.17 Addition of Grignard Reagents to Nitriles
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50. 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.
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51. 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
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52. Example F3C C N + CH3MgI 1. diethyl ether 2. H3O+, heat F3C CCH3 O
(79%)
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53. Section 20.18 Spectroscopic Analysis of Carboxylic Acid Derivatives
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54. 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
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55. 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
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56. Infrared Spectroscopy
Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching in the cm-1 region.
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57. 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
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58. 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.
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59. 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
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Chemical shift (, ppm) 1

60. The carbon of a CN group appears near  120 ppm.
13C NMR
Carbonyl carbon is at low field ( ppm), but not as deshielded as the carbonyl carbon of an aldehyde or ketone ( ppm).
The carbon of a CN group appears near  120 ppm.
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61. UV-VIS n* absorption: max CH3CCl O CH3COCCH3 O CH3COCH3 O CH3CNH2 O
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62. 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
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63. 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 +
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64. End of Chapter 20
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