Amines

Amines are organic derivatives of ammonia in which one

or more of the hydrogen of ammonia substituted with
alkyl or aryl gp.
Like ammonia, amines contain a nitrogen atom with a
lone pair of electrons, making amines both basic and
nucleophilic, and most of its chemistry depends on the
presence of this lone pair of electrons.
Amines occur widely in all living organism.
Trimethylamine, for instance, occurs in animal tissues and
is partially responsible for the distinctive odor of fish.
Nicotine is found in tobacco and cocaine stimulant found
in south American coca bush.
Amino acids are the building blocks for all proteins.
Cyclic amines bases are the constituents of nucleic acid
 According to the No. of substituents attached
to the nitrogen amines classified, into 1ry, 2ry
or 3ry amine.
R NH2 R N R R N R
H
R
1amine 2amine 3amine

The R gp attached to the nitrogen may be any

combination of alkyl and aryl or part of a ring.
Aliphatic: Common system:
Simple aliphatic amines named by naming the alkyl gp
followed by word (amine).
If the cpd has more than one similar R gp then their No. is
indicated with di or tri.
H H3C N CH3
CH3CH2 NH2 H3C NH2 H3C C NH2 H3C N CH2CH3
H
Ethylamine methylamine CH3
CH3
Ethylmethylamine
trimethylamine
Isopropylamine

CH3

H3C C NH2

CH3
t-butylamine
IUPAC system:
Select the longest chain of the alkane, then replace (e)
with amine e.g ethanamine, (e) retained in di and tri.

CH3CH2 NH2
Ethanamine

In complex structures or compounds with more than

one functinal gp, amino gp considered as substituent in
the parent chain.
OH

1 H H 4
H3C C C CH3 NH2
2 3
NH2 CH3 CH3

2-amino-3-methylbutane 3-amino-4-methylcyclohexanol
 Unsymmetrically substituted secondary and
tertiary amines named as N-substituted
primary amines.
The largest alkyl gp chosen as parent name
and other alkyl gps are N-substituents (N
because they are attached to nitrogen)
H3C CH3 1 H 3 4
N H3C C C CH3
2
H2
N
H3C CH3

N,N-dimethyl-2-butanamine

N,N-dimethylcyclohexanamine
 Aromatic amines:
Simple aromatic amine is aniline , in the presence of methyl
gp on the ring , amine name changed to toluidine , and it is
of three isomers o,m and p toluidine.
NH2
NH2

o, m, or p-toluidine

CH3
Aniline
2ry and 3ry amine usually named as derivative to aniline.
H 3C
NH

N-methylaniline
 Physical properties:

The bonding in alkylamine similar to ammonia.

The nitrogen is sp3-hybridized, tetrahedral shape with the
unshared electrons occupies one of the tetrahedral corners
and the angle about 109.

Due to the presence of nitrogen in the structure of amine.

Then amine are polar with high boiling point than alkane of
comparable Mwt., but less than that of alcohol.
 1ry amine is of the highest boiling point then 2ry which higher
than 3ry.
like alcohols amines of five carbon and less are souble in
water , can form hydrogen bond with water except 3ry
amines, and increase in Mwt decrease amines solubility in
water.
Small Mwt amines have ammonia like odor, high Mwt
amines have fishlike aromas which's responsible about fish
odor due to their presence in a high concentration in their
tissues.
 Basicity of amines:
As in case of ammonia amines have unshared pair of
electrons which can be donated to an acid, the
strength of basicity can be determined by their
dissociation in water.
The higher Kb indicate strong base, pKb also used to
compare the basicity and its more convenient, the
smaller PKb is the stronger basicity.
 H3C H3C
NH + HCl NH2 Cl

H3C H3C

NH3 PKb 7.74

CH3-NH2 PKb 3.36
CH3-NH-CH3 PKb 3.29
(CH3)3N PKb 4.29
Methy amine is stronger base than ammonia, whereas
dimethylamine which possess two methyl gp slightly
stronger than 1ry methyl amine, trimethylamine that has
three methyl gp attached to the nitrogen is weaker base
than both 1ry and 2ry amine.
 The releasing of electron by methyl gp makes 1ry
amine strong than ammonia and to some extend
the strength of 2ry amine over the 1ry.
In case of the 3ry amine, although it has three
release gp but its basicity is less, this is because the
releasing effect of methyl groups is offset by an
other factor mainly the diminished hydration.
Hydration is the driving force of ionization in water
i.e stabilization of the ion formed.
Trimethyl gp makes a shading effect to the
trimethylammonium ion that will be form that
means less hydration, more over the increase in No.
of hydrogen around nitrogen increase hydrationin
,then 1ry ammonium ion there is three hydrogen,
whereas in 2ry ammonium ion is two, in case of
3ry ammonium ion only one hydrogen which of
the less hydration.
 Aromatic amines:
Generally aromatic amines less basic than aliphatic amines
because of resonance.
NH2
NH2 NH2
NH2

Aniline PKb 9.38 the unshared es not localized on the

nitrogen it is distributed all over the ring, therefore less
available for donation to an acid.
Effect of substituents on basicity of aromatic amines:

NH2 NH3

+ H

Groups that decrease the intensity of the positive charge on

the anilinium ion it increase its stability, therefore electron
releasing gp increase basicity while electron withdrawing
decrease the basicity.
Isolation of amines from neutral compouds
(e.g amides) using their basicity:
 In addition to their behaviour as bases, primary and
secondary amines can acts also as very weak acids because
of an N-H proton can be removed by sufficiently strong
base
 Preparation of amines:

Unfortunately, these reaction dont stop cleanly after

single alkylation, because ammonia and primary amine have
similar reactivity therefore there is a chance of poly alkylation
e.g when 1-bromooctane treated with twofold of ammonia the
result is:
 Aryl halides can not inter such reaction to give amine
unless it contains strong electron withdrawing gp at
ortho and para.
NO2 NO2

O2N Cl + NH3 O2N NH3 Cl

 As the alkylation of ammonia is not a suitable method
in laboratory for synthesis of 1ry amine, it just used in
industry.
The best methods used for amine preparation:
1) The Azide synthesis:
.. + ..
N=N=N azide ion very strong nucleophile but not
basic, can attack alkyl halide to give alkyl azide, alkyl
azide is no longer nucleophile, therefore over
alkylation as in case of ammonia will not take place.
Reduction of alkyl azide chemically with LiAlH4 or
catalytically it gives 1amine.
This reaction need special control, because the
handling of the low molecular weight and highly
explosive azide need special and careful handling.
Another method for synthesis 1ry amines is
2) Gabriel amine synthesis:
When phthalic anhydride is heated in presence of ammonia
phthalimide is obtained.
O O

300 C KOH
O + NH3 NH

O O
 O O

H2 O
N K + R X N R
OH

O O
O
K-phthalimide N-alkylphthalimide
O
R NH2 +
O

This method give pure 1amine

 3) Reductive amination:
Many aldehydes and ketones can be converted in a single
step reaction to amine by reduction with H2 and catalyst in
presence of NH3 or 1amine, in a reaction known as
reductive amination.
Example, amphetamine a central nervous system stimulant,
is prepared commercially by reductive amination of phenyl-
2-propanone with ammonia, using hydrogen gas over a
nickel catalyst as reducing agent or NaBH4 a chemical
reducing agent.
 O NH NH2
H2 / Ni
R C R + NH3 R C R R C R
H

intermediate imine
Sec. Alkyl gp difficult to be
synthesized by amminolysis as
elimination will predominate.
O
NH2

K2Cr2O7 / H+ NH3

H2 / Pt
OH

cyclohexylamine
Br

PBr3 NH3
 Biologically in synthesis of proline amino acid,
glutamate 5-semialdehyde undergo internal imine
formation which then reduced by nicotinamide
adenine dinucleotide, NADH a biological reducing
agent to proline amino acid
 4) Reduction of Nitro compounds:
Reduction of nitro cpd namely the aromatic one, catalytically
or chemistry by metals in presence of acid (Zn or Sn or Fe) in
presence of HCl.
NO2 NH2

Zn, HCl

CH3 CH3

If suitable amount of ammonium bisulphide NH4SH is used

with a dinitrobenzene, reduction to one nitro gp will take
place. NO2 NH2

NH4SH

NO2 NO2
 5) Reduction of nitrile:

This is a method by which amine with one carbon more than

alkylhalide start with is produced.
If we used AgCN instead of NaCN, isonitrile is formed rather
than nitrile, as in case of AgCN the bond is ambedant
(neither acid nor a base), and electron localized on the
nitrogen, therefore attack as nucleophile through nitrogen
site, whereas in case of NaCN the CN attack as cyano ion.
Ag C LiAlH4 R C N CH3
N + R CH2Cl R C N C H2 H
H2
2 amine
isonitrile

6) Hofmann degradation of amides: (rearrangement)

This method leads to amine having one carbon less than
amide start with.
The mechanism of the reaction involve migration of alkyl
group from carbonyl carbon, to the adjacent nitrogen, and
the carbonyl leave as CO2, this reaction take place in
presences of Hypo halide.

O
NaOH / Br2
R C NH2 R NH2 + Na2CO3 + NaBr + H2O
 Mechanism:
O
O O
R C NH2 OH Br Br OH
R C NH R C N Br
H

O
spontaneous H2O
R C N Br R N C O
Alkylisocyanate

R N C O
R NH2 + CO2
H O
H

carbamic acid
 Despite the complex mechanism Hofmann
rearrangement gives high yield of both aryl amines and
alkyl amines, example, the appetite-suppressant drug
phentermine is prepared commercially by this method
 7) Curtius rearrangement:
O O

R C Cl NaN3 R C N N N R N C O
+

H 2O
Acy azide
R N C O
R NH2 + CO2 H O
H
Unstable carbamic acid
 Rxn of amines:
1) Basicity:
Amines react as base donate its electron to an
acid to give a salt.

NH2 NH3 Cl

+ HCl

water insol Anilinium chloride

water sol
2)
1, 2, & 3 amines alkylation by using alkyl halide
results in 2, 3, and quaternary ammonium salt
respectively.
Acylation of amines: Conversion into amides
 O
NH3
S
O Cl N H
S
H
R NH2 O
S
N R
H

R N R
H O
S
N R
R
 When benzene sulphonyl chloride or benzoyl chloride is use for
acylation reaction NaOH is used to neutralized HCl that formed,
this known as Schotten Baumann techniques.
Reaction of benzene sulphonyl chloride with amine 1, 2, and 3
is used as method to differentiate between them.
1 amine give sulphonamide with acidic hydrogen which form
with NaOH a salt soluble in water, addition of HCl converted to
sulphonamide which is insoluble in water.
2 amine give a sulphonamide contains no acidic hydrogen i.e
insoluble in NaOH, addition of HCl still insoluble.
3 amine give benzene sulphonyl trialkylammonium salt which is
unstable hydrolyze in NaOH into sulphonic acid sodium salt and
3mine which is insoluble in NaOH, addition of HCl it is soluble.
This properties and the different behavior of amines in their
reaction with benzene sulphonyl chloride, known as Hinsberg test,
and its used to differentiate between amines classes.
 Quaternary ammonium salts:

Nomenclature:
CH3
Cl
Propyl trimethyl ammonium chloride
H3C C C N CH3
H2 H2
CH3

The hydrogen of the ammonium ion NH4+ is

replaced with alkyl gps, then naming of quaternary
ammonium salt by naming these alkyl gp followed
by ammonium salt.
 Preparation of quaternary ammonium salts:

Prepared from reaction of 3ry amine with alkyl halide or 1ry

amine in presence of excess alkyl halide.

CH3 CH3
Cl
H3C N + H3C C C Cl H3C C C N CH3
H2 H2 H2 H2
CH3 CH3
 Reaction of quaternary ammonium salts:

React with silver oxide Ag2O in presence of H2O to

give quaternary ammonium hydroxide which is
strong base comparable to NaOH in its basicity, the
basicity is due to hydroxyl ion.

CH3 CH3
Cl OH
Ag2O / H2O
H3C C C N CH3 H3C C C N CH3
H2 H2 (AgOH) H2 H2
CH3 CH3
 Filtration of the silver halide, whereas the quaternary
ammonium hydroxide is soluble in water, can be obtained by
evaporation of water.
Quaternary ammonium hydroxide can be subjected to
Hofmann elimination which take place according to
Hofmann elimination rule, which is elimination from charged
molecule to obtain least substituted alkene.
Highly substituted alkene is usually obtained from
uncharged molecule as per Saytezeff rule of alcohol
dehydration to alkenes.
CH3 CH3 H3C C C CH2 + H3C C C CH3
OH 150 C H2 H H H
H3C C C N CH3
H2 H 5%
95%
CH3
 Mechanism:

OH
H
CH2 CH3 CH3

H3C C C N CH3 H3C C C CH2 + H3C N

H2 H H2 H
CH3
CH3

Elimination of - hydrogen the 1ry as been more

acidic, if there is no 1ry then elimination of the 2ry
- hydrogen which has a priority over the 3ry.
 CH3 CH3
CH3
CH3I Ag2O / H2O
excess 150 C
N (AgOH)
N
H N
H3C CH3
I H 3C CH3
OH
CH3
CH3 CH3
CH3I
CH3 Ag2O / H2O CH3
excess 150 C
N
H3C CH3 N (AgOH) N
H3C CH3 H3C CH3
I
OH

CH3 CH3

N
+ H3C CH3

This method known as Exhaustive methylation, it is a method of

determination of amines.
Its follows the conversion of all hydrogen of amine to methyl gps,
then subject it to Hofmann elimination to determine alkyl gp
attached to the nitrogen in the amine start with.

CH3
H2C

H3C C C N CH3
H2 H2

Biological Hofmann elimination type to fumarate and

adenosine base in the nucleic acid synthesis processes.
What product would you expect from Hofmann elimination
of the following amine?

Hints:
 Ring Substitution in aromatic amines:
NH2, NHR and NR3 are powerful activating groups and o, p
director.
NHCOCH3 acetamido gp moderate activating which result in
modulating of the ring reaction by substitution even those
impossible will be possible by acetylation of the amino gp.
N+R3 quaternary ammonium salt nitrogen with actual positive
charge its powerful deactivating gp meta director.
1) Halogenations:
Aromatic amine are highly activated, therefore substitution
occurs at all the available o & p positions.
NH2 NH2

Br Br
Br2

Fe

Br
 Introduction of one bromo group is possible by reducing the
activity of amino gp to amide (Acetamido), that is by
acylation of the amino gp.
One bromo gp enter p position due to the steric effect, due
to the bulkiness of the acetamido gp, and its less activation
to the ring compared with amino gp

O O
NH2 HN C CH3 HN C CH3

(CH3CO)2O Br2

Fe

Br
When p-position is occupied the reaction goes according to priority of
the directors:

O O

HN C CH3 HN C CH3

Br
Br2

Fe

CH3 CH3
 2) Nitration:
Nitric acid is not only nitrating agent its also oxidizing agent,
result in oxidizing the highly reactive amino benzene result
in tary material in addition to its reaction with the amino
gp, been an acid converte it to salt i.e deactivating gp.
To solve such problem we protect the amino gp by acylation,
which reduce the activity of the gp and convert it to non
basic cpd the amide.

O O
NH2 HN C CH3 HN C CH3 NH2

(CH3CO)2O HNO3 H2O

H2SO415C OH

NO2 NO2
 Friedel Craft Rxn:
The impossible Friedel-Craft alkylations and acylation on
aniline, will be possible on N-acetylarylamine and it take
place normally.
Example, benzoylation of acetanilide (N-acetylaniline under
Friedel-Craft conditions gives 4-aminobenzophenone in 80%
yield after hydrolysis
 An other example for modulating the reactivity of amino
substituted benzene by electrophilc substitution is in the
synthesis of sulfa drugs, example sulphanilamide which used
as antibacterial
 Primary arylamines react with nitrous acid (HNO2) at
(0 5) C , to yield stable arenediazonium salts in a
process called a diazotization reaction.

Nitrous acid (HONO) is a weak unstable acid. It is

always prepared by treating sodium nitrile (NaNO2)
with an aqueous solution of strong acid.
HCl(aq) + NaNO2(aq) HNO2(aq) + NaCl(aq)
 N-nitrosoamines:
N-nitrosoamines are very powerful carcinogens which, which
may be found in many foods, especially in cooked meats that
have been cured by sodium nitrite.
Sodium nitrite is used to many meats e.g bacon, ham,
frankfurters, sausages to inhibit growth of Clostridium
botulinium that produce toxin and also NaNo2 keep red
meat not to turn brown.
FDA reduce the permitted amount of nitrite from 200 parts
to 50 125
Alkylamines also react with nitrous acid, but the alkane
diazonium products of these reactions are unstable, instead
are very reactive to isolate, they lose nitrogen instantly to
yield a carbocation, which give all carbocation reaction (can
be attacked by nucleophile or base)

HNO2
R NH2 R N N HSO4 R + N2
H2SO4
 Secondary amines both aryl and alkyl react with nitrous acid
to yield N-nitosoamines, which usually separate from
aqueous solution as oily yellow liquids.
 Tertiary arylamines react with nitrous acid to
form p-nitroso amine or ortho if p-position is
not available, it is an electrophilc aromatic
substitution.
 Arenediazonium salts are extremely useful because the diazonio
group (N2) can be replaced by a nucleophile in a substitution
reaction

Nucleophiles can be halide, Hydride, cyanide and hydroxide.

Thus among formation of aryldiazonium salt different kinds of
substituted benzenes can be produce.
The overall sequences 1- nitration 2- reduction 3- diazotization
and then 4- nucleophilic substitution, which is the most flexible
method of aromatic substitution

NO2
NH2
N N

HNO3
HNO2
H2SO4
H2SO4
 Sandmeyer reaction (replacement with Cl, Br CN):

Aryl chloride and bromide are prepared by reaction of an

arenediazonium salt with the corresponding copper(I)halide,
CuX, a process called the Sandmeyer reaction
Aryl iodides can be prepared by direct reaction with NaI or
KI without using a copper (I) salt
Replacement by-F:
The diazonium group can be replaced by fluorine by treating the
diazonium salt with fluoroboric acid (HBF4).
The diazonium fluoroborate that precepitate is isolated, dried and
heated until decomposed to aryl fluoride
 Similar treatment of an arenediazonium salt with CuCN
yields the nitrile, ArCN, which can further converted into
other functional groups such as Carboxyl.
Example Sandmeyer reaction of o-methylbenzene
diazonium bisulphite with CuCN yield o-methylbenzo-
nitrile, which can be hydrolyzed to give o-methylbenzoic
acid.
 It is not possible to synthesize o-methyl benzoic acid
from o-xylene by the usual side chain oxidation with
KMnO4 oxidize, because of oxidation of both methyl
groups to carboxyl.
CH3 COOH

CH3 COOH
KMnO4
 2- replacement of diazonium salt with OH
The diazonio group can also be replaced by OH to yield a
phenol in Sandmeyer variation method, this by treating
arenediazonium salt with copper (I) oxide in an aqueous
solution of copper (II) nitrate, this reaction is an important
reaction, as a very few reactions available for introducing a
OH onto aromatic ring.
 Replacement by hydrogen: Deamination by
diazotization
Arenediazonium salts react with hypophosphorous acid (H3PO2) to yield
products in which the diazonium groups replaced by H.
Since we usually begin a synthesis by nitration of aromatic ring then
reduction to NH2 so replacing diazo gp by H is a replace to NO2 or NH2.
We can introduce amino group to influence the orientation of a
subsequent reaction, later we can remove the amino group i.e
deamination e.g synthesis of m-bromotoluene.
 Arenediazonium ions are weak electrophiles, they react with
highly reactive aromatic compounds such as phenol and
tertiary arylamine to yield azo compounds.
This electrophilic aromatic substitution is often called a
diazo coupling reaction and the reaction usually occur at p-
position, only ortho can take place if p-position is blocked.
 Azo-coupled products are widely used as dyes for textiles because their
extended conjugated electron system causes them to absorb in the
visibl e region of the electromagnetic spectrum i.e coloured compounds
e.g p-(dimethylamino)azobenzene is a bright yellow