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Course Code : Z0218

Course : Organic Chemistry


Year : 2014/2015
Amines
Course Outline
Structure & classification
Nomenclature
Physical Properties
Basicity of Amines
IMAGE(S)
Amines as Natural Products
Introduction

Amines:
derivatives of ammonia (NH3) with one or more alkyl or
aryl group bonded to the N atom
contain N attached to one or more alkyl (aliphatic amine)
or aromatic groups (aromatic amine).

amino
R-NH2 group

NH
CH22 CH3
CH3-NH2 CH3-NH-CH3

Aliphatic amine
Ethylbenzene
Aromatic amine
Structure &
Classification

Amines are categorized by the number of alkyl groups


attached to the nitrogen:

1 (primary amine) - one alkyl bonds to N atom R-NH2


2 (secondary amine) - two alkyl bonds to N atom R2-NH
3 (tertiary amine) - three alkyl bonds to N atom R3-N
4 (quaternary amine salt) - four alkyl or aryl bonds to N atom
R4N+
Structure & Classification

Amines are further divided into aliphatic, aromatic, and


heterocyclic amines:
a. Aliphatic amine: An amine in which nitrogen is bonded
only to alkyl groups.
b. Aromatic amine: An amine in which nitrogen is bonded
to one or more aryl groups.

CH3 CH3
:

NH2 N-H CH2 -N-CH3


:

:
Aniline N-Methylaniline Benzyldimethylamine
(a 1 aromatic amine) (a 2 aromatic amine) (a 3 aliphatic amine)
Structure & Classification

c. Heterocyclic amine:
An amine in which nitrogen is one of the atoms of a ring.

N N N N
H H H
Pyrrolidine Piperidine Pyrrole Pyridine
(heterocyclic aliphatic amines) (heterocyclic aromatic amines)
Structure & Classification

Example:
Classify each amino group by type.

CH3
N
H
H COOCH3
(a) (b) N (c)
N
CH3 O C6 H5
H N
(S)-Coniine (S)-Nicotine Cocaine O
Nomenclature

Common name
names the alkyl groups bonded to Nitrogen, followed by
the suffix amine. Arrange the alkyl groups into
alphabetical order.
Give prefixes di-, tri-, tetra- to describe the number of
identical substituent
Nomenclature

For complicated structures, the NH2 group is called the amino


group.
It is treated like any other substituent, with a number or other
symbol indicating its position on the ring or carbon chain.

2o and 3o amines are named by classifying the N atom (together


with its alkyl groups ) as an alkylamino group.
The largest or most complicated alkyl group is taken to be the
parent molecule.
Nomenclature

Aromatic amines (amines with benzene ring):


Generally known by historical names
e.g.: phenylamine known as aniline. Its derivatives
named as derivatives of aniline
The IUPAC system retains the name aniline

NH2 NH2 NH2 NH2

OCH3
NO2 CH3
Aniline 4-Nitroaniline 4-Methylaniline 3-Methoxyaniline
(p-Nitroaniline) (p-Toluidine) (m-Anisidine)
Nomenclature

Heterocylic amines:
When N is one of the atoms of a ring.
The heteroatom is usually assigned position number 1
Nomenclature

IUPAC name
The longest continuous chain of carbon atoms become
the root name.
Change the e ending in the alkane to amine.
Show the position of the amino group along the chain.
The position of amino group should be the smallest.
Give numbers for the other substituents and the prefix
N- is used for each substituent on Nitrogen
Nomenclature

Among the various functional groups, -NH 2 is one of the


lowest in order of precedence.

Amine vs alcohol Amine vs acid

OH OH
H2 N H2 N COOH
NH2
2-Aminoethanol (S)-2-Amino-3-methyl- 4-Aminobenzoic acid
1-butanol
Nomenclature

When four groups are bonded to nitrogen, the compound


is named as a salt of the corresponding amine.
Chirality of amines

If the unshared pair of electrons on nitrogen consider


as the fourth group, then the arrangement of groups
around N is approximately tetrahedral.
A tetrahedral amine with three different substituents
(and a lone pair) bonded to N is nonsuperimposable on
its mirror image. So it has chirality center (chiral) and
exists as a pair of enantiomer (two enantionmers)
Chirality of amines

However, they cannot be resolved because the enantiomers


are interconvert rapidly each other. The interconversion
takes place by nitrogen inversion, in which the lone pair of
electron moves from one face of the molecule to the other.
e.g.: interconversion of (R) and (S) ethylmethylamine
The N-atom is sp2 hybridized in transition state, and the non
bonding electrons occupy a p orbital.
Chirality of amines

In naming the enantiomers of chiral amines, use the


Cahn-Ingold-Prelog convention with the nonbonding
electron pair as the lowest priority:
1. Amines whose chirality stems from the presence of
asymmetric carbon atoms.
. Most chiral amines fall into this group.
. Nitrogen is not the chirality center so the Nitrogen
inversion is irrelevant
e.g.: butan-2-amine can be resolved into enantiomers
because the 2-butyl group is chiral
Chirality of amines

2. Quaternary ammonium salts with asymmetric nitrogen


atoms.
Inversion of configuration is not possible because there is
no lone pair to undergo nitrogen inversion.
e.g.: the methyl ethyl isopropyl anilinium salts can be
resolved into enantiomers.
Chirality of amines

3. Amines that cannot attain the sp2 hybrid transition


state for nitrogen inversion.
If the N atom is contained in a small ring, it is
prevented from attaining the 120o bond angles that
facilitate inversion.
It has higher activation energy for inversion, the
inversion is slow, and the enantiomers may be
resolved.
e.g.: chiral aziridines can be resolved into enantiomers
Physical properties

1. Have unpleasant odors (rotting fish like ammonia).


2. Belongs to polar compounds
. difference in electronegativity between N - H (3.0 2.1
= 0.9)
. Has large dipole moment of the lone pair of electrons
adds to the dipole moments of the C N and H N
bonds.
3. 1 and 2 amines have hydrogen bonds (N-H).
4. 3 amines do not form hydrogen bonds, because the
have no N-H bonds
Physical properties

5. Boiling points: hydrocarbons < amines < alcohols


BP of 1o and 2o amines < than alcohols of similar
molecular weights
BP of 1o and 2o amines > than ethers of similar
molecular weights
BP of 3o amines < than 1o and 2o amines of similar
molecular weights
Physical properties

6. Soluble in alcohols; lower molecular-weight amines (up


to 4 carbon atoms) are relatively soluble in water.
7. Weaker hydrogen bonds than alcohols (O-H) of similar
molecular weights.
Physical properties
Chemical properties

1. weak bases (like ammonia)


react with acid to form water-soluble salt

H H
.. ......O H
-
N.
. +
CH3 + H ..
OH CH3 N H

H H

Some amines present in our blood and make it


approximately basic (pH = 7.4).
Chemical properties

2. Aliphatic amines are weak bases by comparison with


inorganic bases such as NaOH, they are strong bases
among organic compounds.

3. Aliphatic amines are stronger bases than aromatic


amines (slightly stronger than NH3)

Class pKb Example Name


Aliphatic 3.0 - 4.0 CH3 CH2 NH2 Ethanamine Stronger base
Ammonia 4.74
Aromatic 8.5 - 9.5 C6 H5 NH2 Aniline Weaker base
Examples

Complete each acid-base reaction and name the salt


formed.

(a) (CH3 CH2 )2 NH + HCl

(b) + CH3 COOH


N
Examples (cont)

.
Solutions:

(a) (CH3 CH2 ) 2 NH + HCl (CH3 CH2 ) 2 NH2 +Cl-


Diethylammonium
chloride

(b) + CH3 COOH CH3 COO-


N N+
H Pyridinium acetate
Basicity

Amines is nucleophile (Lewis base) because has lone


pair of nonbonding electrons that can form a bond with
an electrophile

Amines can also act as a Bronsted-Lowry base by


accepting a proton from a proton acid
Basicity

Amines can abstract a proton from water, giving an ammonium


ion and a hydroxide ion.

The equilibrium constant for the reaction is called the base-


dissociation constant (Kb)

Values of Kb for most amines are fairly small (< 10-3) and the
equilibrium for this dissociation lies toward the left
Aqueous solutions of amines are distinctly basic
Basicity

Ammonium ion and amine act as a conjugate acid-base


pair.
Ammonium ion is a conjugate acid (has Ka or pKa) while
amine is a conjugate base (has Kb or pKb).

Strongly basic amine has a weakly acidic ammonium ion


Weakly basic amine has a strongly acidic ammonium ion
Basicity
Basicity

Effects on basicity
Some factors influence amine basicity:
1. Substitution by alkyl groups
e.g. : ammonia (NH3) vs methylamine (CH3NH2)
Simple alkylamines are generally stronger bases than
ammonia
Alkyl groups are electron-donating (-CH3, -NH2, -OCH3)
toward cations, it increase the basicity of amines
Electron-withdrawing groups such as halogens, nitro
groups, and carbonyl groups, decrease the basicity of
aromatic amines by a combination of resonance and
inductive effects.
Basicity

Methylamine has a methyl group (with lone pair of


electron) to help stabilize the positive charge on nitrogen.
The stabilization lowers the potential energy of the
methylammonium cation, making methylamine a stronger
base than ammonia.
Basicity

Basicity of 1o, 2o and 3o amines


Ammonium ions are charged, and strongly solvated by
water, and the energy of solvation contributes to the stability
of molecule.
Additional alkyl groups around the ammonium ions of 2o and
3o decrease the number of water molecules that can
approach closely and solvate the ions.
2o alkylamine is stronger base than 1o amine, and 1o amine
has stronger base compare with 3o amine. Inductive
stabilization and steric hindrance of solvation are balanced
for 2o alkylamines which make the molecule is stronger
bases than 1o or 3o alkylamines.

(aniline
) (cyclohexyla
mine)
Basicity

2. Resonance effects
Aromatic amines (anilines and their derivatives) or
arylamines are weaker bases than simple aliphatic amines.
The reduced basicity is due to resonance delocalization of
the non bonding electrons in the free amine.
Stabilization of the reactant (free amine) makes the amine
less basic. In aniline, overlap between the aromatic ring and
the orbital containing nitrogens lone pair stabilizes the lone
pair and makes it less reactive. The overlap is lost in the
anilinium ion
Basicity

e.g. : pyrrole. Pyrrole is aromatic and a very weak base


because the non bonding electrons on nitrogen are located in
a p orbital, which contribute to the aromatic sextet. When the
pyrolle nitrogen is protonated, pyrorole loses its aromatic
stabilization. Therefore, protonation on nitrogen is
unfavorable
Basicity

3. Hybridization effects
Electrons are held more tightly by s orbital.
Unsaturated amines tend to be weaker bases than simple
aliphatic amines.
In pyridine, the nonbonding electrons occupy an sp2 orbital
with greater s character and more tightly held electrons
than those in sp3 orbital of an aliphatic amine.
Pyridines nonbonding electrons are less available for
bonding to a proton. Pyridine does not lose its aromaticity
on protonation, however and it is much stronger base than
pyrrole
Basicity

The effect of increased s character on basicity is even more


pronounced in nitriles with sp hybridization.
e.g.: acetonitrile (pKa = 24) is a weak base. A concentrated
mineral acid is required to protonate acetonitrile.
Basicity

All amines are weak bases, and aqueous solutions of


amines are basic.

H H
+ -
CH3 -N + H-O-H CH3 -N-H O-H
H H
Methylamine Methylammonium hydroxide

It is common to discuss their basicity by reference to


the acid ionization constant of the conjugate acid.

CH3NH3+ + H2 O CH3 NH2 + H3 O+


+
[CH3NH2][H3 O ]
Ka = + = 2.29 x 10-1 1 pKa = 10.64
[CH3 NH3 ]
Basicity

Using values of pKa, we can compare the acidities of amine


conjugate acids with other acids.

+ -
CH3NH2 + CH3 COOH CH3NH3 + CH3COO pK eq = -5.88
pKa 4.76 pKa 10.64 Keq = 7.6 x 10
5

(stronger (weaker
acid) acid)
Basicity

Basicity of aliphatic vs aromatic amines

Note that pKa + pKb = 14


Aliphatic amines:
Amine Structure pKa pKb
Ammonia NH3 9.26 4.74
Primary Amines
methylamine CH3 NH2 10.64 3.36
ethylamine CH3 CH2 NH2 10.81 3.19 Stronger bases
cyclohexylamine C6 H1 1 NH2 10.66 3.34
Secondary Amines
dimethylamine (CH3 ) 2 NH 10.73 3.27
diethylamine (CH3 CH2 ) 2 NH 10.98 3.02
Tertiary Amines
trimethylamine (CH3 ) 3 N 9.81 4.19
triethylamine (CH3 CH2 ) 3 N 10.75 3.25
Basicity

Aromatic amines:

Amine Structure pK a of Conjugate Acid


Aromatic Amines
Aniline NH2 4.63

4-Methylaniline Weaker bases


CH3 NH2 5.08

4-Chloroaniline Cl NH2 4.15

4-Nitroaniline O2N NH2 1.0

Heterocyclic Aromatic Amines


Pyridine N 5.25

N
Intermediate
Imidazole
6.95
N
H
Basicity

1. Aromatic amines are considerably weaker bases than aliphatic amines.

NH2 + H2 O
+
NH3 OH
-
pK a = 10.66

Cyclohexylamine Cyclohexylammonium
hydroxide

NH2 + H2 O NH3 + OH- pK a = 4.63

Aniline Anilinium hydroxide

Aromatic amines are weaker bases than aliphatic amines because of two
factors:
Basicity

a. Resonance stabilization of the free base, which is lost on


protonation.
H H+ H H+H H +H
N H N N N

. . H unhybridized 2p orbital of N
H
. . ..
H
H . . N
H
nitrogen is sp2 hybridized
H H

b. The greater electron-withdrawing inductive effect of the


sp2-hybridized carbon of an aromatic amine compared with
that of the sp3-hybridized carbon of an aliphatic amine.
Basicity

3-nitroaniline is a stronger base than 4-nitroaniline.

O2N

NH2 O2N NH2

3-Nitroaniline 4-Nitroaniline
pK a 2.47 pK a 1.0

delocalization of the nitrog en


lone pair onto the oxyg en atom s
of the nitro group

O -O
+
+N NH2 +N NH2
O
- -O

Cannot do this kind of resonance in 3


Basicity

2. Heterocyclic aromatic amines are weaker bases than


heterocyclic aliphatic amines.

N
N N N
H H
Piperidine Pyridine Imidazole
pKa 10.75 pKa 5.25 pK a 6.95

3. Pyridine is a weaker base than heterocyclic aliphatic


amines because the free electron pair on N lies in an sp2
hybrid orbital (33% s character) and is held more tightly
to the nucleus than the free electron pair on N in an sp3
hybrid orbital (25% s character).
Basicity

In pyridine, the unshared pair of electrons on N is not part


of the aromatic sextet.

. . an sp2 hybrid orbital; the electron


H H
. . pair in this orbital is not a
.
part of the aromatic sextet
H . N :

H H nitrogen is sp2 hybridized


Basicity

Imidazole
Which N lone pair is protonated? The one which is not part
of the aromatic system.

This electron pair Aromaticity is


is not a part of the maintained when
aromatic sextet imidazole is protonated
H
:
This electron N N+
pair is a part + H2 O + OH-
of the aromatic
:

:
N N
sextet
H H
Imidazole Imidazolium ion
Basicity

Guanidine
Guanidine is the strongest base among neutral organic
compounds.
+
NH NH2
-
H2 N C NH2 + H2 O H2 N C NH2 OH+ pKa = 13.6
Guanidine Guanidinium ion

The basicity is due to the delocalization of the positive


charge over the three nitrogen atoms.
+
:

:
NH2 NH2 NH2
+ +
:

:
H2 N C NH2 H2 N C NH2 H2 N C NH2

Three equivalent contributing structures


Basicity

4. Arylamines (aromatic amines) are less basic than


alkylamines

5. Amines vs amides (RCONH2)


Amides are nonbasic
amides are poor nucleophiles. Amides is stabilized by
delocalization of the Nitrogen lone-pair electrons
through orbital overlap with the carbonyl group.
Amides are more stable and less reactive than amines
(has resonance stabilization)
Reaction with acids

All amines, whether soluble or insoluble in water, react


quantitatively with strong acids to form water-soluble
salts.
OH OH
HO NH2 HO NH3+ Cl-
H2 O
+ HCl
HO HO
(R)-Norepinephrine (R)-Norepinephrine hydrochloride
(only slightly soluble in water) (a water-soluble salt)
Reaction with acids

Most amines (containing more than six carbon atoms are


relatively insoluble in water) but can be diluted in
aqueous acid to form their corresponding dissolved
ammonium salts. can be used for functional groups
test of amines

Amine salts:
ionic, high-melting, non volatile solids
soluble in water than parent amines
slightly soluble in nonpolar organic solvents
Reaction with acids

Separation and purification of an amine and a neutral compound.


Reaction with acids

Separation and purification of an amine and a neutral compound.


Reaction with acids

Separation and purification of an amine and a neutral compound.

amine
salts
Synthesis of amines

Amines can be synthesis using the following methods:


nucleophilic ring opening of epoxides by ammonia and
amines.
addition of nitrogen nucleophiles to aldehydes and
ketones to form imines
reduction of imines to amines
reduction of amides to amines by LiAlH4
reduction of nitriles to a 1 amine
nitration of arenes followed by reduction of the NO 2
group to a 1 amine
Synthesis of amines

1. Alkylation of ammonia by SN2 substitution

SN2 CH3 NH3 + Br-


CH3 Br + NH3
Methylammonium
bromide

Unfortunately, such alkylations give mixtures of products through


a series of proton transfer and nucleophilic substitution reactions.
Synthesis of amines

2. Acylation-reduction of amines

Acylation : addition of an acyl group by


replacing a hydrogen atom
Acylation of an amine gives an amide

acyl
Synthesis of amines

3. Reduction of azides
(Azide = compound having azido group, N3)

4. Reduction of nitriles
Synthesis of amines

5. Reduction of amides

6. Nucleophilic aromatic substitution


Reaction of amines

1. Alkylation

2. Acylation to form amides


Reaction of amines

3. Hoffman elimination

Hoffman elimination usually gives the least substituted alkenes

Hofmanns rule: any elimination that occurs preferentially to give


the least substituted alkenes as the major product is said to follow
Hofmanns rule.
Reaction of amines

4. Cope elimination of tertiary amine oxide


Cope elimination is a thermal decomposition of 3 o amine oxide.

Cope elimination usually gives the least highly substituted


alkenes

5. Reaction with HNO2


This reaction is useful for amine synthesis. HNO 2 is unstable,
generated in situ (in the reaction mixture), by mixing NaNO2
with cold, dilute HCl.
Reaction of amines

In acidic solution, HNO2 is protonate and lose water to give


the nitrosonium ion (+N = O)
The nitrosonium ion (+N = O) is a reactive intermediate in
most reaction of amines with nitrous acid

a. Reaction with 1o amines formation of diazonium


salts

Mechanism of diazotization of an amines:


1o amines + HNO2 (= nitrosonium ion) N nitrosamine
N-nitrosamine + H2O diozonium cation (R N+ N)
Reaction of amines

Since the alkanediazonium salts are unstable and can be


decompose to nitrogen and carbocation, the diazotization
of 1o alkylamines is not widely used for synthesis.

1o aromatic amines with HNO2


The -N2+ group of an arenediazonium salt can be replaced
in a regioselective manner by these groups.
H2O
Ar-OH
HBF4 Schiemann
Ar-F
reaction
HCl, CuCl Ar-Cl
HNO2 + (-N ) Sandmeyer
. Ar-NH2
0-5C
Ar-N2 2 HBr, CuBr Ar-Br reaction
KCN, CuCN
Ar-CN
KI Ar-I
H3PO2
Ar-H
Reaction of amines

1 aromatic amine converted to a phenol.


NH2 OH
Br Br
1. HNO2
2. H2O, heat
CH3 CH3
2-Bromo-4- 2-Bromo-4-
methylaniline methylphenol

Tiffeneau-Demjanov reaction:
Treatment of a -aminoalcohol with HNO2 gives a ketone
and N2.
OH O

CH2 NH2 + HNO2 + H2 O + N2

A-aminoalcohol Cycloheptanone
(1-aminomethyl-
Reaction of amines

Mechanism of Tiffeneau Demjanov:


Reaction with NO+ gives a diazonium ion.
Concerted loss of N2 and rearrangement followed by proton
transfer gives the ketone.

:
:

: OH :O-H
HNO 2 + -N2
CH2NH2 CH2 N N:

(A diazonium ion)

proton transfer

:
+ O H O
:

:
:O H
to H2O
+ CH2 CH2

A resonance-stabilized cation Cycloheptanone

Similar to pinacol rearrangement


Reaction of amines

1 aliphatic amines give a mixture of unrearranged and


rearranged substitution and elimination products, all
of which are produced by way of a diazonium ion and
its loss of N2 to give a carbocation.
Diazonium ion: An RN2+ or ArN2+ ion
Reaction of amines

b. Reaction with 2o amines formation of N


nitrosamines

Nnitrosamines are stable under the reaction of


conditions.
Small quantities of Nnitrosamines have been shown to
cause cancer.
Reaction of amines

Sodium nitrite use for meat preservation when combines


with stomach acid (HCl) can convert the amines to form N
nitrosamines which can cause cancer.

N-H + HNO2 N-N=O + H2 O

Piperidine N-Nitrosopiperidine (carcinogen


s)

Mechanism:
+ (1) (2) +
+ N O + + H O H


N N N H


H N=O



H N=O






H O

H
Reaction of amines

c. Reaction with 3o amines


3 Aliphatic amines, whether water-soluble or water-
insoluble, are protonated to form water-soluble salts.
3 Aromatic amines: NO+ is a weak electrophile and
participates in Electrophilic Aromatic Substitution

1. NaNO2 , HCl, 0-5C


Me2 N Me2 N N=O
2. NaOH, H2O
N,N-Dimethylaniline N,N-Dimethyl-4-nitrosoaniline
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