Amination

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1. Amines, reactions
Amines are similar to ammonia in their reactions.
Like ammonia, amines are basic.
Like ammonia, amines are nucleophilic and react with
alkyl halides, acid chlorides, and carbonyl compounds.
The aromatic amines are highly reactive in electrophilic
aromatic substitution.

2. Amine, reactions:
1.As bases
2.Alkylation
3.Reductive amination
4.Conversion into amides
5.EAS
6.Hofmann elimination from quarternary
ammonium salts
7.Reactions with nitrous acid

3. 1.As bases
a) with acids
b) relative base strength
c) Kb
d) effect of groups on base strength

4. with acids
NH
2+ HCl NH
3
+
Cl
-
(CH
3CH
2)
2NH+ CH
3COOH (CH
3CH
2)
2NH
2
+
,
-
OOCCH
3
anilinium chloride
diethylammonium acetate

5. relative base strength
RNH
2
> NH
3
> ArNH
2
K
b
ionization of the base in water
:Base + H
2
O H:Base
+
+ OH
-
K
b
= [ H:Base
+
] [ OH
-
] / [ :Base ]
K
b
aliphatic amines 10
-3
– 10
-4
ammonia 1.8 x 10
-5
anilines 10
-9
or less

6. Why are aliphatic amines more basic than ammonia?
NH
3
+ H
2
O  NH
4
+
+ OH
-
R-NH
2
+ H
2
O  R-NH
3
+
+ OH
-
The alkyl group, -R, is an electron donating group.
The donation of electrons helps to stabilize the ammonium
ion by decreasing the positive charge, lowering the ΔH,
shifting the ionization farther to the right and increasing the
basicity.

7. Why are aromatic amines less basic than aliphatic amines?
R-NH
2
+ H
2
O  R-NH
3
+
+ OH
-
NH
2
+ H
2O
NH
3
+ OH
NH
2 NH
2 NH
3
NH
3
NH
2 NH
2
NH
2 resonance stabilization of the
free base, increases the ΔH,
shifts the ionization to the left,
decreasing base strength.

8. Effect of substituent groups on base strength:
NH
2
+ H
2O
NH
3
+ OH
G G
Electron donating groups will stabilize the anilinium ion,
decreasing the ΔH, shifting the ionization farther to the right and
making the compound a stronger base.
Electron withdrawing groups destabilize the anilinium ion,
increasing the ΔH, shifting the ionization towards the reactants,
making the compound a weaker base.

9. Common substituent groups:
-NH
2
, -NHR, -NR
2
-OH
-OR
-NHCOCH
3
electron donating
-C
6
H
5
groups
-R
-H
-X
-CHO, -COR
-SO
3
H electron withdrawing
-COOH, -COOR groups
-CN
-NR
3
+
-NO
2

10. Number the following in decreasing order of base strength (let
#1 = most basic, etc.
NH
3
NH
2 NH
2 NH
2
NH
2
NO
2
OCH
3
4 1 5 3 2

11. 2. Alkylation (ammonolysis of alkyl halides)
RNH
2
R-X
R
2NH
R-X
R
3N
R-X
R
4N
+
X
-
1
o 2
o 3
o
4
o
salt
S
N2: R-X must be 1
o
or CH
3
CH
3CH
2CH
2CH
2Br
NH
3
CH
3CH
2CH
2CH
2NH
2
n-butylamine

12. CH
3CH
2CH
2NH
2
CH
3Cl
CH
3CH
2CH
2NHCH
3
n-propylamine methyl-n-propylamine
NH
2
2 CH
3CH
2Br
N
Et
Et
aniline N,N-diethylaniline
H
2
CNH
2
benzylamine
(xs) CH
3I H
2
CN
CH
3
CH
3
CH
3 I
benzyltrimethylammonium iodide

13. 3. Reductive amination
CO
H
2, Ni
or NaBH
3CN
CHNHR+ RNH
2
CO
H
2, Ni
or NaBH
3CN
CHNR
2+ R
2NH 3
o
amine
2
o
amine

14. CCH
2CH
3
O
propiophenone
+ CH
3CH
2NH
2
NaBH
3CN
CHCH
2CH
3
NH
CH
2CH
3
1-(N-ethylamino)-1-phenylpropane
O
cyclohexanone
CH
3NH
2, H
2/Ni
NHCH
3
cyclohexylmethylamine

15. 4.Conversion into amides
R-NH
2
+ RCOCl  RCONHR + HCl
1
o
N-subst. amide
R
2
NH + RCOCl  RCONR
2
+ HCl
2
o
N,N-disubst. amide
R
3
N + RCOCl  NR
3
o

16. NH
2+ (CH
3CO)
2O
H
NCCH
3
O
N-phenylacetamide
C
O
Cl
(CH
3CH
2)
2NH + C
O
NCH
2CH
3
CH
2CH
3
N.N-diethyl-m-toluamide
NCH
3
CH
3
+CH
3C
O
Cl
NR
H
3C H
3C
DEET

17. Conversion into sulfonamides
R-NH
2
+ ArSO
2
Cl  ArSO2NHR + HCl
1
o
N-subst.sulfonamide
R
2
NH + ArSO
2
Cl  ArSO
2
NR
2
+ HCl
2
o
N,N-disubst.sufonamide
R
3
N + ArSO
2
Cl  NR

18. Schotten-Baumann technique: reactions of aromatic acid
chlorides are sped up by the addition of base.
R-NH
2
+ ArSO
2
Cl + KOH  ArSO2NHR
1
o
acidic
ArSO
2
NR
water soluble salt
R
2
NH + ArSO
2
Cl + KOH  ArSO
2
NR
2
+ HCl
2
o
N,N-disubst.sufonamide
water insoluble

19. Hinsberg Test:
unknown amine + benzenesulfonyl chloride, KOH (aq)
Reacts to produce a clear solution and then gives a
ppt upon acidification  primary amine.
Reacts to produce a ppt  secondary amine.
Doesn’t react  tertiary amine.

20. NH
2 N
NCH
3
CH
3
+ SO
2Cl S
O
O
KOH
(CH
3CH
2)
2NH SO
2Cl
KOH
+ SO
2Cl
KOH
+ S
O
O
N
CH
2CH
3
CH
2CH
3
NR
water sol.
ppt

21. sulfanilamide “magic bullet” antibiotic
NH
2
SO
2
NH
2

22. N
NN
N
OH
H
2N
H
2
C
H
N C
O
H
NCH
COOH
CH
2CH
2COOH
folic acid
H
2N COOH
p-aminobenzoic acd
H
2N SO
2NH
2
sulfanilamide

23. 5.EAS
-NH
2
, -NHR, -NR
2
are powerful activating groups and
ortho/para directors
a) nitration
b) sulfonation
c) halogenation
d) Friedel-Crafts alkylation
e) Friedel-Crafts acylation
f) coupling with diazonium salts
g) nitrosation

24. a) nitration
NH
2
HNO
3
H
2SO
4
TAR!
(CH
3CO)
2O
NHCOCH
3
HNO
3
H
2SO
4
NHCOCH
3
NO
2
+ ortho-
H
2O,OH
-
D
NH
2
NO
2

25. b) sulfonation
NH
2
+ H
2SO
4
NH
3
SO
3
cold H
2SO
4
NH
3
HSO
4

26. c) halogenation
NH
2
+ Br
2, aq.
NH
2
Br Br
Br
no catalyst needed
use polar solvent
Br
2,Fe
Br
HNO
3
H
2SO
4
Br
NO
2
+ ortho-
H
2/Ni
Br
NH
2
polyhalogenation!

27. NH
2
Cl
2 (aq.)
NH
2
CH
3
Cl
Cl
CH
3
o-toluidine
bright yellow!
Swimming pool test kit for chlorine:

28. e)Friedel-Crafts alkylation
NR with –NH
2
, -NHR, -NR
2
NH
2
CH
3
+ CH
3CH
2Br, AlCl
3 NR
Do not confuse the above with the alkylation reaction:
NH
2
CH
3
+ CH
3CH
2Br
NHCH
2CH
3
CH
3

29. f)Friedel-Crafts acylation
NR with –NH
2
, -NHR, -NR
2
NH
2
CH
3
+ NR
Do not confuse the above with the formation of amides:
NH
2
CH
3
NHCCH
3
CH
3
H
3CC
O
Cl
AlCl
3
+H
3CC
O
Cl
O

30. g) nitrosation
N
H
3CCH
3
NaNO
2, HCl
N
H
3CCH
3
N
O
The ring is sufficiently activated towards EAS to react
with the weak electrophile NO+

31. h) coupling with diazonium salts  azo dyes
NH
2
CH
3
+
N
2
Cl
benzenediazonium
chloride
CH
3
NH
2
N
N
an azo dye

32. 6.Hofmann elimination from quarternary hydroxides
step 1, exhaustive methylation  4
o
salt
step 2, reaction with Ag
2
O  4
o
hydroxide + AgX
step 3, heat to eliminate  alkene(s) + R
3
N
CH
3CH
2CH
2CH
2
(xs) CH
3I
CH
3CH
2CH
2CH
2
NH
2
N
CH
3
CH
3
CH
3
I
-
CH
3CH
2CH
2CH
2
N
CH
3
CH
3
CH
3
I
-
Ag
2O
CH
3CH
2CH
2CH
2
N
CH
3
CH
3
CH
3
OH
-
+ AgI
CH
3CH
2CH
2CH
2
N
CH
3
CH
3
CH
3OH
D
CH
3CH
2CH=CH
2 + (CH
3)
3N

33. CH
3CH
2CHCH
3
NH
2
+ (xs) CH
3I CH
3CH
2CHCH
3
N
CH
3
CH
3H
3C I
-
CH
3CH
2CHCH
3
N
CH
3
CH
3H
3C I
-
Ag
2O CH
3CH
2CHCH
3
N
CH
3
CH
3H
3C OH+ AgI
CH
3CH
2CHCH
3
N
CH
3
CH
3H
3C OH
D
CH
3CH
2CH=CH
2 + CH
3CH=CHCH
3
+ (CH
3)
3N
chief product
Hofmann orientation

34. 7. Reactions with nitrous acid
NH
2
+ HONO NNdiazonium salt
R-NH
2+ HONO N
2 + mixture of alchols & alkenes
primary amines
secondary amines
H
NR+ HONO NR
N
O
N-nitrosamine
tertiary amines
NR
R
+ HONO
NR
R
N
O
p-nitrosocompound

35. note: 90% of all tested nitrosamines are carcinogenic in man.
Many nitrosamine cancers are organ specific. For example,
dimethylnitrosamine causes liver cancer while the
nitrosamines in tobacco smoke cause lung cancer.
Sodium nitrite (“cure”) is used as a preservative in meats such
as bacon, bologna, hot dogs, etc. to kill the organism
responsible for botulism poisoning. In the stomach, the nitrous
acid produced from sodium nitrite can react with secondary
and tertiary amines to form nitrosamines. To reduce the
formation of nitrosamines, ascorbic acid (Vitamin C) is now
added to foods cured with sodium nitrite.
Nitrosamines are also found in beer!

36. Amines, reactions
Amines are similar to ammonia in their reactions.
Like ammonia, amines are basic.
Like ammonia, amines are nucleophilic and react with
alkyl halides, acid chlorides, and carbonyl compounds.
The aromatic amines are highly reactive in electrophilic
aromatic substitution.

37. Amine, reactions:
1.As bases
2.Alkylation
3.Reductive amination
4.Conversion into amides
5.EAS
6.Hofmann elimination from quarternary
ammonium salts
7.Reactions with nitrous acid