Transcript 19_14_16rw

19.14
Amides
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Physical Properties of Amides
Amides are less reactive toward nucleophilic
acyl substitution than other acid derivatives.
Physical Properties of Amides
Amides are capable of hydrogen bonding.
Physical Properties of Amides
Amides are less acidic than carboxylic acids.
Nitrogen is less electronegative than oxygen.
Preparation of Amides
Amides are prepared from amines by acylation
with:
Acyl chlorides (Table 19.1)
Anhydrides (Table 19.2)
Esters (Table 19.4)
Preparation of Amides
Amines do not react with carboxylic acids to give
amides. The reaction that occurs is proton-transfer
(acid-base).
O
RCOH + R'NH2
O
–
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
O
RCNHR' + H2O
Example
O
COH +
H2N
225°C
O
+ H2O
CNH
(80-84%)
19.15
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
RCNHR' + H2O + H
O
+
+
RCOH + R'NH3
Hydrolysis of Amides
In basic solution the carboxylic acid product
is deprotonated to give a carboxylate ion.
O
RCNHR'
O
–
+ HO
–
RCO
+ R'NH2
Example: Acid Hydrolysis
O
O
CH3CH2CHCNH2
CH3CH2CHCOH
H2O
H2SO4
heat
+
+ NH4 HSO4–
(88-90%)
Example: Basic Hydrolysis
O
NH2
CH3CNH
O
KOH
H2O
heat
Br
CH3COK +
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
O
RCNH2 + H2O
H+
OH
RC
OH
NH2
Water adds to the
carbonyl group of the
amide.
This stage is
analogous to the acidcatalyzed addition of
water to a ketone.
Second Stage: Cleavage of Tetrahedral
Intermediate
O
RCOH
+
+ NH4
H+
OH
RC
OH
NH2
Mechanism of Formation
of
Tetrahedral Intermediate
Step 1
H
••
O ••
H
O ••
+
H
RC
• NH2
•
••
+O
RC
•• NH2
H
H
•• O •
•
H
Step 1
••
•• O
H
RC
+ NH2
••
+O
RC
•• NH2
H
Carbonyl oxygen is
protonated because
cation produced is
stabilized by electron
delocalization
(resonance).
Step 2
••
•• OH
H
+
O ••
RC
•• NH2
••
+O
RC
•• NH2
H
H
H
•• O •
•
H
Step 3
••
•• OH
RC
H
+
O ••
H
H
•• NH2
•• O •
•
H
••
•• OH
RC
•• NH2
H
O ••
••
+
H O ••
H
H
Cleavage of Tetrahedral
Intermediate
Step 4
••
•• OH
••
RC
H2N
H
OH
+
••
•• O •
•
H
H
••
•• OH
RC
H2N ••
H
O ••
••
H
H
O ••
+
H
Step 5
••
•• OH
••
RC
H2N
OH
+
••
H
••
•• OH
RC
+ ••
OH
••
+
•• NH3
Step 6
••
•• OH
••
RC
H2N
OH
+
••
H
+ NH
4
••
•• OH
RC
+ ••
OH
••
+
H3O
+
•• NH3
Step 6
••
•• OH
RC
+
••
+ OH
RC
••
OH
••
••
OH
••
Step 6
H
••
O ••
••
O+
H
H
••
H
O
RC
••
••
OH
••
••
+O
H
RC
••
OH
••
H
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
O
RCNH2 + H2O
HO–
OH
RC
OH
NH2
Water adds to the
carbonyl group of the
amide.
This stage is
analogous to the
base-catalyzed
addition of water to a
ketone.
Second Stage: Cleavage of Tetrahedral
Intermediate
O
–
RCO
+ NH3
HO–
OH
RC
OH
NH2
Mechanism of Formation
of
Tetrahedral Intermediate
Step 1
••
O ••
H
•• O •
•
•• –
RC
• NH2
•
– ••
•• O ••
RC
•• NH2
H
O ••
••
Step 2
••
•• –
•• O •
•
H
••
•• O
H
O ••
H
H
O ••
RC
••
•• NH2
H
– ••
•• O ••
RC
•• NH2
H
O ••
••
Dissociation of
Tetrahedral Intermediate
Step 3
••
•• OH
••
RC
H2N
H
OH
+
••
•• O •
•• • –
H
••
•• OH
RC
H2N ••
H
O ••
••
H
H
O ••
••
Step 4
••
O ••
H
•• –
•• O •
•
H
••
•• O
H
••
RC
OH
••
H3N +
H
••
O ••
RC
•• O
••
H
•• NH3
Step 5
••
O ••
RC
•• O •• –
••
HO–
••
O ••
RC
•• O
••
H
•• NH3
19.16
Lactams
Lactams
Lactams are cyclic amides. Some are industrial
chemicals, others occur naturally.





N
O
-Caprolactam*: used to
prepare a type of nylon
H
*Caproic acid is the common name for hexanoic acid.
Lactams are cyclic amides. Some are industrial
chemicals, others occur naturally.
O
C6H5CH2CNH


N
O
S
CH3
CH3
CO2H
Penicillin G: a -lactam antibiotic
(2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic acid