Chemistry of Amides

 Amides are abundant in all living organisms…

proteins, nucleic acids, and other pharmaceut
icals have amid functional groups

1
 Amides
 Thefunctional group of an amide is an acyl grou
p bonded to a nitrogen atom.
• drop -oic acid from the name of the parent acid and ad
d -amide. (For the common acid name, drop -ic of the a
cid name and add -amide.)
• an alkyl or aryl group bonded to the N: name the group
and show its location on nitrogen by N-.

O OH OC H3
C
HC
3NH
2 C
HC
3 -
N H
-C-
N
C
H3 C
H3

A c
et
amid
e N-
M eth
yla
cet
am id
e N ,N-
D im
e t
hyl-
(
a 1
°amid
e) (
a 2
°amide) f
ormam ide(DM F)
(a3°a mide)
ethanamide
18-2
 AMIDA
TATA NAMA
 Suatu amida adalah suatu senyawa yang mempunyai suatu nitroge
n trivalen yang terikat pada suatu gugus karbonil.
 Suatu amida diberi nama asam karboksilat induknya, dengan meng
ubah imbuhan asam....oat (atau –at) menjadi –amida.

O O

H
2
H
3C N
H2 H
3C C C N
H2
H
2
I
U P
AC: E
ta
namid
a B
uta
namid
a
T
riv
ia
l: A
se
ta
m id
a B
utir
amid
a
 Amida dengan substituen alkil pada nitrogen diberi tambah
an N-alkil didepan namanya, dengan N merujuk pada atom
nitrogen.

O O

H H C N C
H
C N C
H 3
3

C
H3
N
-
m e
ti
lbe
nz
ami
da N
,
N -
dime
ti
lfo
rma
mid
a
 Amides; Lactams
 Lactams: A cyclic amides are called lactams.
• Name the parent carboxylic acid, drop the suffix -ic aci
d and add -lactam.
 O
 O  2
3 1
2
3
1
 4 NH
NH 5 6
H3C  
3-Butanolactam
6-Hexanolactam
 
-Butyrolactam)
-Caprolactam)

Indicates where the N is located.

18-5
 Imides
 Thefunctional group of an imide is two acyl grou
ps bonded to nitrogen.
• Both succinimide and phthalimide are cyclic imides.
O O

NH NH

O O
Succinimide Phthalimide

18-6
 AMIDA
 Ikatan
amida cukup stabil seperti yang terdapat pada ikatan antar asam a
mino dalam protein.
RO RO RO RO

H
N
2 CCO
H H
NCCNCCNCC
H H HH HH
a
s
ama
mi
no s
u
at
upr
ot
ei
n (
po
li
ami
da)

Amida merupakan basa yang sangat lemah (bandingkan dengan amina).

+-
CH N
3H 2 H
Cl C
HN
3H3C
l
m
et
ila
m in
a m
et
ila
mon
iu
mklo
rid
a

O
H
Cl t
ida
kt
erja
dip
en
gga
ra
man
C
H
3C N
H2

Hal ini disebabkan adanya resonansi pada amida, sehingga atom N tidak ber
sifat basa dan tidak bersifat nukleofilik

O O
k
u
ran
gb
a
sad
ib
an
d
in
gk
a
n
C C N
i
tr
og
en
am
i
na
R N
H2 R N
H2
Amides: resonance

18-8
Amides; Characteristics

18-9
 Acidity of N-H bonds
 Amides are comparable in acidity to alcohols.
• Water-insoluble amides do not react with NaOH or othe
r alkali metal hydroxides to form water-soluble salts.
 Sulfonamides and imides are more acidic than a
mides.
O O
O
O
S
NH2 N
H N
H
C
HC
3NH
2
O
O O
A
ce
tam
ideB
en
zen
es
ulf
o n
amid
eSu
cc
inimid
ePh
tha
limid
e
p
Ka15
-1
7 pK 1
0 pK 9.7 pK 8
.3
a a a

18-10
 Acidity of N-H bonds
 Effect of neighboring carbonyl groups.

18-11
1.0
 Acidity of N-H
• Imides such as phthalimide readily dissolve in aqueou
s NaOH as water-soluble salts.
O O
- +
N
H +N
aOH NN
a+H
2O

O O
pKa8 .3 pK
a1 5.7
(s trong(ser
trong er(weaker (weaker
acid) bas e) bas e) acid)

18-12
Acidity of N-H bonds
 Imides are more acidic than amides because
1. the electron-withdrawing inductive of the two adjacent
C=O groups weakens the N-H bond, and
2. More resonance delocalization of the negative charge.

O O O

N N N

O O O
A
re
son
anc
e-s
tab
iliz
eda
nio
n

18-13
 Preparation of Amides
 Prepared by reaction of an acid chloride with ammoni
a, monosubstituted amines, or disubstituted amines

14
 PEMBUATAN AMIDA
Dari halida asam atau anhidrida asam dengan amonia, mono- atau dwi
substitusi amina (bagaimana dengan amina tersier ?)
O O
SOCl2
C C
R OH R Cl
asamkarboksilat klorida asam

NR'2
NH3 NH2R'

O O O

C C C
R NH2 R NHR' R NR'2

Pemanasan asam amino karboksilat akan membentuk laktam (amida

O
siklis)
O C
+
N
H2 H,p
ans H
a 2C
HO
C N
H 2
C
HC
2HC
2 H
2C
H2 O
H H
2C
C
H
2
a
sa
m-am
in
obu
tir
at 
-bu
tir
ola
kta
m
 REAKSI AMIDA
1. Hidrolisis ( RCONH2  RCOOH )
Amida mengalami hidrolisis menjadi asam karboksilat dan amina
bila dipanaskan dalam larutan asam maupun basa. Hidrolisis ami
da oleh asam atau basa berjalan searah (irreversible)
Mekanisme reaksinya mirip hidrolisis ester tetapi perlu kondisi re
aksi lebih kuat.
a. Hidrolisis oleh asam
O O
C C
N
H2 O
H
H
S
2O4
+ -
H
O N
H
4HSO
4
2

b
e
nz
am
id
a a
s
amb
e
nz
oa
t a
mo
ni
umh
i
dro
ge
ns
ul
fat

b. Hidrolisis oleh basa

O O
N
a
OH C
H
3N
H
2

C
H
3C
H
2 N
H
CH
3 C
H
3C
H
2 O
N
a
N
-
met
i
lpr
op
an
a
mi
da N
a
pr
op
an
o
at m
e
t
i
la
mi
na
(1.a) Acidic Reaction with H2O - Amides
 Hydrolysis
of an amide in aqueous acid requires
one mole of acid per mole of amide.
• Reaction is driven to completion by the acid-base react
ion between the amine or ammonia and the acid.
O O
H
2O +-
NH+H
2 2
O
+H
Cl O
HN
+H4C
l
heat
P
h P
h
2-Phenylbutanam
2-Phenyl i

18-17
(1.b) Basic Reaction with H2O - Amides
 Hydrolysis
of an amide in aqueous base requires
one mole of base per mole of amide.
• Reaction is driven to completion by the irreversible for
mation of the carboxylate salt.
O O
H
O
C
HC
3NH +N
aH2 C
O H
CO- ++
3 Na H2N
h
ea
t
N-
Phe
nyl
ethan
ami
de S
od
iu
m A
ni
li
ne
(
N-Ph
en
ylac
eta
mid
e, a
ce
ta
te
Ac
et
anil
ide
)

18-18
Mechanism: Acidic H2O - Amides
• Step1: Protonation of the carbonyl oxygen gives a reso
nance-stabilized cation intermediate.
O +
RCNH
2 +HOH

H
+H H H
O O O
+
RCN
H2 RC N
H2 RCNH2 +H
2O
+
R
eso
nan
ce-
sta
biliz
edc
atio
n in
ter
m e
d ia
te

18-19
 Acidic H2O - Amides
• Step 2: Addition of water (a nucleophile) to the carbonyl carbon (a
n electrophile) followed by proton transfer gives a TCAI.

proton
O
H H transfer
O O
H f
+ O to N+
RCN
H+
2 O
H RCN
H2 RCN
H3
H +
O O
H H H
• Step 3: Collapse of the TCAI and proton transfer. (Elimination)

H
O +H
O O
+ +
RCN
H3 RC+NH
3 RCO
H+N
H4

O
H O
H

18-20
 Reactions of Amides
(Acidic Hydrolysis)
 Heating in either aqueous acid or aqueous base prod
uces a carboxylic acid and amine
 Acidic hydrolysis by nucleophilic addition of water to t
he protonated amide, followed by loss of ammonia

21
 Basic Hydrolysis of Amides
 Addition of hydroxide and loss of amide ion

22
Mechanism: Reaction with Basic H2O - Amides

Amide

hydroxide ion

Dianion!

18-23
2. REDUKSI ( RCONH2  RCH2NH2 )
 Amida direduksi oleh LiAlH4 menghasilkan amina
 Reduksi terhadap laktam menghasilkan amina siklis

O 1
.LiA
lH,e
4 te
r
C
H3(C
H2)10 C N
HCH
3 2
.HO C
H3(C
H2)10 C
H2 N
HCH
3
2

N
-me
tild
ode
kan
amid
a N
-me
tild
ode
sila
m in
a

O
1
.LiA
lH,e
4 te
r
2
.HO N
HCH
3
N
HCH
3 2

N
-me
tilp
ipe
rid
in
N
-mtil-
e -va
lero
lak
tam
(2) Reduction: Conversion of Amid
es into Amines
 Reduced by LiAlH4 to an amine rather than an alcoh
ol
 Converts C=O  CH2

25
 Mechanism of Reduction
 Addition of hydride to carbonyl group
 Loss of the oxygen as an aluminate anion to give an i
minium ion intermediate which is reduced to the amin
e

26
Uses of Reduction of Amides
 Works with cyclic and acyclic
 Good route to cyclic amines

27
 PENISILIN DAN SEFALOSPORIN
Adalah antibiotika yang mengandung cincin β-laktam.
Penisilin ditemukan oleh Alexander Fleming (1928); diisolasi dari jamur Penic
illium notatum. Dapat menghambat pertumbuhan bakteri Staphylococcus au
reus.
Cincin β-laktam (dari Penisilin maupun Sefalosporin) berinteraksi dengan enzi
m transpeptidase sehingga enzim tersebut tidak aktif. Bakteri akan mati kar
ena kekurangan enzim transpeptidase yang diperlukan untuk pembentukan
dinding sel bakteri.
H
2 H HH H
2 H HH
C N C N
S C
H3
C C
C
O C N C
H O C N
3 C
H3
O O
- +
C
OONa
C
OOH
c
inin
c -la
kta
m

B
enzylpe n ic
illin Se faleksin
=Pe
nicillinG (se n
y a
w ago lon
g a
ns efa
lo
sporin
)
aktivitasantibakterile
bihpo
ten
diban d
ingp enis
ilin
 SENYAWA TERKAIT DENGAN AMI
DA
Kelebihan Nitrogen pada metabolisme protein oleh hewan tingkat tinggi d
iekskresi sebagai urea. Pada hewan tingkat rendah ekskresi berupa amo
nia, sedangkan pada reptil dan burung mengekskresi guanidin.
O O N
H

H
N
2 CN
H2 R
N
2 CN
R2 H
N
2 CN
H2

u
r
ea u
r
eat
er
su
bs
t
i
tus
i g
u
an
i
di
n

Urea dipakai untuk sintesis golongan obat barbiturat (untuk obat penenang
) dengan cara mereaksikan dengan dietil malonat

O O
N
H C
HC
3HO
2 C H
NC
2 C
HCHO
3 2
OC C
H OC C
H2
2
CHC
3HO
2H
2
N
H2 C
HC
3HO
2 C H
NC
O O
u
r
ea d
i
eti
lma
l
ona
t a
s
amb
ar
bi
tur
at
SENYAWA YANG TERKAIT DENGAN AMIDA
Struktur parsial golongan contoh
O O
CN amida H 3 C C NH 2

O O
laktam
CN NH

H
O O O N O
imida
C N C

O O
N C N urea H 2N C NH 2

O O
N C O
karbamat H 2N C OCH 3
= uretan
O O
S N sulfonamida S NH 2
O O