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.

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

1. As bases

a) with acids
b) relative base strength
c) Kb

d) effect of groups on base strength

with acids

NH2

+ HCl

NH3+Clanilinium chloride

(CH3CH2)2NH + CH3COOH

(CH3CH2)2NH2+, -OOCCH3
diethylammonium acetate

relative base strength

RNH2 > NH3 > ArNH2
Kb

ionization of the base in water

:Base + H2O

H:Base+ + OH-

Kb = [ H:Base+ ] [ OH- ] / [ :Base ]

Kb
aliphatic amines

10-3 10-4

ammonia

1.8 x 10-5

anilines

10-9 or less

Why are aliphatic amines more basic than ammonia?

NH3 + H2O NH4+ + OHR-NH2 + H2O R-NH3+ + 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 H,
shifting the ionization farther to the right and increasing the
basicity.

Why are aromatic amines less basic than aliphatic amines?

R-NH2 + H2O R-NH3+ + OHNH3

NH2
+ H2O

NH2

NH2

+ OH

NH2

NH2

NH3

NH2

NH3

resonance stabilization of the

free base, increases the H,
shifts the ionization to the left,
decreasing base strength.

Effect of substituent groups on base strength:

NH2

NH3
+ H2O

+ OH
G

Electron donating groups will stabilize the anilinium ion,

decreasing the H, shifting the ionization farther to the right and
making the compound a stronger base.
Electron withdrawing groups destabilize the anilinium ion,
increasing the H, shifting the ionization towards the reactants,
making the compound a weaker base.

Common substituent groups:

-NH2, -NHR, -NR2

-OH
-OR
-NHCOCH3
-C6H5
-R
-H
-X
-CHO, -COR
-SO3H
-COOH, -COOR
-CN
-NR3+
-NO2

electron donating
groups

electron withdrawing
groups

Number the following in decreasing order of base strength (let

#1 = most basic, etc.

NH2

NH2

NH2

NH2

NH3
NO2

OCH3

2. Alkylation (ammonolysis of alkyl halides)

RNH2
1o

R-X

R2NH

R-X

R3N
3o

R-X

R4N+X4o salt

SN2: R-X must be 1o or CH3

CH3CH2CH2CH2Br

NH3

CH3CH2CH2CH2NH2
n-butylamine

CH3CH2CH2NH2
n-propylamine

NH2

CH3Cl

CH3CH2CH2NHCH3
methyl-n-propylamine

2 CH3CH2Br

aniline

Et
N
Et
N,N-diethylaniline

(xs) CH3I
H2
C NH2
benzylamine

H2 CH3
C N CH3
CH3
I
benzyltrimethylammonium iodide

3. Reductive amination

C O + RNH2

C O + R2NH

H2, Ni

CH NHR

2o amine

CH NR2

3o amine

or NaBH3CN

H2, Ni
or NaBH3CN

O
CCH2CH3 + CH3CH2NH2
propiophenone

cyclohexanone

NaBH3CN

CH2CH3
NH
CHCH2CH3

1-(N-ethylamino)-1-phenylpropane

CH3NH2, H2/Ni

NHCH3

cyclohexylmethylamine

4. Conversion into amides

R-NH2 + RCOCl RCONHR + HCl
1o

N-subst. amide

R2NH + RCOCl RCONR2 + HCl

2o

R3N
3o

N,N-disubst. amide

+ RCOCl NR

NH2

O
H
N C CH3

+ (CH3CO)2O

N-phenylacetamide
O
C
Cl

(CH3CH2)2NH +
H3C

H3C

O
C
N CH2CH3
CH2CH3

N.N-diethyl-m-toluamide
DEET
O
N CH3
CH3

CH3C

Cl

NR

Conversion into sulfonamides

R-NH2 + ArSO2Cl ArSO2NHR + HCl

1o

N-subst.sulfonamide

R2NH + ArSO2Cl ArSO2NR2 + HCl

2o

R3N

N,N-disubst.sufonamide
+ ArSO2Cl NR

Schotten-Baumann technique: reactions of aromatic acid

chlorides are sped up by the addition of base.
R-NH2 + ArSO2Cl + KOH ArSO2NHR
1o

acidic
ArSO2NR
water soluble salt

R2NH + ArSO2Cl + KOH ArSO2NR2 + HCl

2o

N,N-disubst.sufonamide
water insoluble

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.
Doesnt react tertiary amine.

O
S
O

KOH
NH2

SO2Cl

N
water sol.

O
CH2CH3
S N
CH2CH3
O

KOH
(CH3CH2)2NH +

SO2Cl

ppt
KOH
N CH3
CH3

SO2Cl

NR

sulfanilamide

magic bullet

NH2

SO2
NH2

antibiotic

OH
N

N
H2N

H2 H
C N

O
H COOH
C N CH
CH2CH2COOH

N
folic acid

H2N

COOH

p-aminobenzoic acd

H2N

SO2NH2
sulfanilamide

5. EAS
-NH2, -NHR, -NR2 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

a) nitration
NH2
HNO3

TAR!

H2SO4
(CH3CO)2O
NHCOCH3

NH2

NHCOCH3

HNO3

H2O,OH-

H2SO4

NO2
+ ortho-

NO2

b) sulfonation
NH3

NH2
+ H2SO4

SO3
cold H2SO4
NH3 HSO4

c) halogenation
NH2

NH2
Br

Br

polyhalogenation!

+ Br2, aq.
Br
no catalyst needed
use polar solvent
Br
Br2,Fe

Br
HNO3

Br
H2/Ni

H2SO4
NO2
+ ortho-

NH2

Swimming pool test kit for chlorine:

NH2
CH3

o-toluidine

NH2
Cl2 (aq.)

Cl

CH3

Cl
bright yellow!

e) Friedel-Crafts alkylation
NR with NH2, -NHR, -NR2
NH2
CH3
+ CH3CH2Br, AlCl3

NR

Do not confuse the above with the alkylation reaction:

NH2

NHCH2CH3
CH3

CH3
+ CH3CH2Br

f) Friedel-Crafts acylation
NR with NH2, -NHR, -NR2
NH2
CH3
+

O
H3C C
Cl

AlCl3

NR

Do not confuse the above with the formation of amides:

O
NH2
NHCCH3
CH3
CH3
O
+ H3C C
Cl

g) nitrosation

H3C

H3C

CH3

CH3

NaNO2, HCl

The ring is sufficiently activated towards EAS to react

with the weak electrophile NO+

h) coupling with diazonium salts azo dyes

N2 Cl

NH2

NH2
CH3

CH3
+
benzenediazonium
chloride
an azo dye

N
N

6. Hofmann elimination from quarternary hydroxides

step 1, exhaustive methylation 4o salt
step 2, reaction with Ag2O 4o hydroxide + AgX

step 3, heat to eliminate alkene(s) + R3N

(xs) CH3I

CH3
CH3CH2CH2CH2 N CH3
CH3

CH3CH2CH2CH2 NH2
CH3
CH3CH2CH2CH2 N CH3
CH3

I-

CH3
CH3CH2CH2CH2 N CH3 OH
CH3

Ag2O

I-

CH3
CH3CH2CH2CH2 N CH3 OH- + AgI
CH3

CH3CH2CH=CH2 + (CH3)3N

CH3CH2CHCH3 + (xs) CH3I

NH2

CH3CH2CHCH3
H3C N CH3
CH3

CH3CH2CHCH3
H3C N CH3
CH3

I-

OH

Ag2O

CH3CH2CHCH3
H3C N CH3
CH3
CH3CH2CHCH3
H3C N CH3
CH3

I-

OH

+ AgI

CH3CH2CH=CH2 + CH3CH=CHCH3
chief product
+ (CH3)3N
Hofmann orientation

7. Reactions with nitrous acid

primary amines

R-NH2

N N

+ HONO

NH2

+ HONO

diazonium salt

N2 + mixture of alchols & alkenes

secondary amines
H
N R

O
N
N R

+ HONO

N-nitrosamine

tertiary amines

N R + HONO
R

O
N

N R
R

p-nitrosocompound

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!

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.

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