Amines

Chapter 23

23-1
Structure & Classification
 Amines are classified as:
• 1°, 2°, or , 3° amines: Amines in which there are 1, 2, or
3 alkyl or aryl groups.
CH3
:

:
CH3 - NH 2 CH3 - NH CH3 - N :
CH3 CH3
Methylamine Dimethylamine Trimethylamine
(a 1° amine) (a 2° amine) (a 3° amine)

23-2
Structure & Classification
 Amines are further divided into aliphatic,
aromatic, and heterocyclic amines:
• Aliphatic amine: An amine in which nitrogen is bonded
only to alkyl groups.
• Aromatic amine: An amine in which nitrogen is bonded
to one or more aryl groups.
CH3 CH3
:

N H2 N -H CH2 - N- CH3
:

:
Aniline N-Methylaniline Benzyldimethylamine
(a 1° aromatic amine) (a 2° aromatic amine) (a 3° aliphatic amine)

23-3
Structure & Classification
• 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)

23-4
Nomenclature
 Aliphatic amines: replace the suffix -e of the
parent alkane by -amine.
amine
NH2

NH2 H2 N
NH2
2-Propanamine (S)-1-Phenyl- 1,6-Hexanediamine
ethanamine

23-6
Nomenclature
 The IUPAC system retains the name aniline.
N H2 N H2 N H2 N H2

OCH3
N O2 CH3
Aniline 4-Nitroaniline 4-Methylaniline 3-Methoxyaniline
(p-Nitroaniline) (p-Toluidine) (m-Anisidine)

23-7
Nomenclature
 Among the various functional groups, -NH2 is one
of the lowest in order of precedence.

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

Amine vs Amine vs
alcohol acid

23-8
Nomenclature
 Common names for most aliphatic amines are
derived by listing the alkyl groups bonded to
nitrogen in one word ending with the suffix
-amine.
amine
H
CH3 NH2 NH2 N Et 3 N

Methylamine tert-Butylamine Dicyclopentylamine Triethylamine

23-9
Nomenclature
 When four groups are bonded to nitrogen, the
compound is named as a salt of the
corresponding amine.
1-ethyl-1-methylpiperidinium chloride

Cl Cl
N N

Cl
tetramethylammonium chloride 1-ethylpyridinium chlride

23-10
Chirality of Amines
• Consider the unshared pair of electrons on nitrogen as
a fourth group, then the arrangement of groups around
N is approximately tetrahedral.
• An amine with three different groups bonded to N is
chiral and exists as a pair of enantiomers and, in
principle, can be resolved.

23-11
Chirality of Amines
• In practice, however, they cannot be resolved because
they undergo inversion, which converts one
enantiomer to the other.

23-12
Chirality of Amines
• Pyramidal inversion is not possible with quaternary
ammonium ions, and their salts can be resolved.

Cl- Cl
-

N N
Et Et
Me Me
S Enantiomer R Enantiomer

23-13
Physical Properties
 Amines are polar compounds, and both 1° and 2°
amines form intermolecular hydrogen bonds.
• N-H- - -N hydrogen bonds are weaker than O-H- - -O
hydrogen bonds because the difference in
electronegativity between N and H (3.0 - 2.1 =0.9) is
less than that between O and H (3.5 - 2.1 = 1.4).

Using bp as an indication of H bonding

CH3 CH3 CH3 NH2 CH3 OH
MW (g/mol) 30.1 31.1 32.0
bp (°C) -88.6 -6.3 65.0

Increasing strength
23-14
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.
CH3 NH3 + + H2 O CH3 NH2 + H3 O+
+
[ CH3 NH2 ] [H3 O ] -1 1
Ka = + = 2.29 x 10 pKa = 10.64
[CH3 NH3 ]
23-15
Basicity
• Using values of pKa, we can compare the acidities of
amine conjugate acids with other acids.
+ -
CH3 NH2 + CH3 COOH CH3 NH3 + CH3 COO pKeq = -5.88
5
pKa 4.76 pKa 10.64 Keq = 7.6 x 10
(stronger (weaker
acid) acid)

23-16
Basicity-Aliphatic Amines
 Aliphatic Amines
• note that pKa + pKb = 14

Amine Structure pK a pK b
Ammonia N H3 9.26 4.74
Primary Amines
methylamine CH3 N H2 10.64 3.36
ethylamine CH3 CH2 NH 2 10.81 3.19 Stronger bases
cyclohexylamine C6 H1 1 NH 2 10.66 3.34
Secondary Amines
dimethylamine ( CH3 ) 2 N H 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

23-17
Basicity-Aromatic Amines
Amine Structure pKa of Conjugate Acid
Aromatic Amines
Aniline NH2 4.63

4-Methylaniline
CH3 NH2 5.08 Weaker
bases
4-Chloroaniline Cl NH2 4.15

4-Nitroaniline O2 N NH2 1.0

Heterocyclic Aromatic Amines

Pyridine N 5.25 Intermediate
N
Imidazole 6.95
N
H
23-18
Basicity-Aromatic Amines
• Aromatic amines are considerably weaker bases than
aliphatic amines.
+ -
NH2 + H2 O NH3 OH pKa = 10.66

Cyclohexylamine Cyclohexylammonium
hydroxide

+ -
NH2 + H2 O NH3 OH pKa = 4.63

Aniline Anilinium hydroxide

23-19
Basicity-Aromatic Amines
 Aromatic amines are weaker bases than aliphatic
amines because of two factors:
• Resonance stabilization of the free base, which is lost
on protonation.
H H+ H H+ H H + H
N H N N N

.
H . H unhybridized 2p orbital of N
. . ..
H
H . . N
H
nitrogen is sp2 hybridized
H H
23-20
Basicity-Aromatic Amines
• 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.

And note the effect of substituents

 Electron-releasing groups, such as alkyl groups,
increase the basicity of aromatic amines.
 Electron-withdrawing groups, such as halogens,
the nitro group, and a carbonyl group decrease
the basicity of aromatic amines by a combination
of resonance and inductive effects.
23-21
Example: Basicity-Aromatic Amines
3-nitroaniline is a stronger base than 4-Nitroaniline.
O2 N

NH2 O2 N NH2

3-Nitroaniline 4-Nitroaniline
pK a 2.47 pKa 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 nitroaniline

23-22
Basicity-Aromatic Amines
 Heterocyclic aromatic amines are weaker bases
than heterocyclic aliphatic amines.
N
N N
N
H H
Piperidine Pyridine Imidazole
pKa 10.75 pK a 5.25 pK a 6.95

23-23
Basicity-Aromatic Amines
• 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

• 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).

23-24
Basicity-Aromatic Amines
 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

23-25
Basicity-Guanidine
 Guanidine is the strongest base among neutral
organic compounds.
+
NH NH2
H2 N C NH2 + H2 O H2 N C NH2 + - pKa = 13.6
OH
Guanidine Guanidinium ion

• Its basicity is due to the delocalization of the positive

charge over the three nitrogen atoms.
+
:

:
N H2 N H2 N H2
+ +
:

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

Three equivalent contributing structures

23-26
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)

23-27
Reaction with acids
 Separation and purification of an amine and a
neutral compound.

23-28
Preparation
 We have already covered these 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 NO2
group to a 1° amine

23-29
Preparation
 Alkylation of ammonia and amines by SN2
substitution.
+ N H
S N2 CH3 NH 3 + Br -
CH3 Br 3
Methylammonium
bromide

• Unfortunately, such alkylations give mixtures of

products through a series of proton transfer and
nucleophilic substitution reactions.
CH3 Br + NH3

+ - + - + - + -
CH3 NH3 Br + (CH3 ) 2 NH2 Br + (CH3 ) 3 NH Br + (CH3 ) 4 N Br

polyalkylations
23-30
Preparation via Azides
 Alkylation of azide ion.
- -: + +
N: - N: -

:
:

:
N3 N N RN 3 R N N
Azide ion An alkyl azide
(a good nucleophile)

+ -
K N3 1 . LiAlH4
Ph CH2 Cl Ph CH2 N 3 Ph CH2 NH2
2 . H2 O
Benzyl chloride Benzyl azide Benzylamine

Overall
Alkyl Halide  Alkyl amine

23-31
Example: Preparation via Azides
• Alkylation of azide ion.
+ -
A rCO 3 H 1. K N3
O
2 . H2 O
Cyclohexene 1,2-Epoxy-
cyclohexane

OH OH
1 . LiA lH4
2 . H2 O
N3 N H2
trans-2-Azido- trans-2-Amino-
cyclohexanol cyclohexanol
(racemic) (racemic)

Note retention of
configuration, trans  trans

23-32
Reaction with HNO2
 Nitrous acid, a weak acid, is most commonly
prepared by treating NaNO2 with aqueous H2SO4
or HCl.
HNO2 + H2 O H3 O+ + NO2 - pK a = 3.37

 In its reactions with amines, nitrous acid:

• Participates in proton-transfer reactions.
• A source of the nitrosyl cation, NO+, a weak
electrophile.

23-33
Reaction with HNO2
 NO+ is formed in the following way.
• Step 1: Protonation of HONO.
• Step 2: Loss of H2O.
(1) + (2)
+ + H O N O
H H O N O
H
+ +
H O + N O N O
H The nitrosyl cation

• We study the reactions of HNO2 with 1°, 2°, and 3°

aliphatic and aromatic amines.

23-34
Tertiary Amines with HNO2
• 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, 0-5°C

Me 2 N Me 2 N N= O
2 . NaOH, H2 O
N,N-Dimethylaniline N,N-Dimethyl-4-nitrosoaniline

23-35
Secondary Amines with HNO2

• 2° Aliphatic and aromatic amines react with NO+ to

give N-nitrosamines.

carcinogens

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

Piperidine N-Nitrosopiperidine
Mechanism:

+ (2) +
••
N O (1)
+ + H O H
•
•

•
•

•• + ••
N N N H
••
••
N= O
•
•

H
•
•

H N= O

•
•
•
•
••
H O
•
•

H 23-36
RNH2 with HNO2
 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

23-37
1° RNH2 with HNO2
 Formation of a diazonium ion.
Step 1: Reaction of a 1° amine with the nitrosyl cation.
H keto-enol
+ tautomerism

:
:
: :
:

:
:
R-NH 2 + : N O : R-N-N=O : R-N=N-O-H

:
A 1° aliphatic An N-nitrosamine A diazotic acid
amine

Step 2: Protonation followed by loss of water.

+
H
H •• + - H2 O
:
:
: :

••
R-N=N-O-H R-N N O-H
••
A diazotic acid + +
R N N R + N N
••

••

••
A diazonium ion A carbo-
cation
23-38
1° RNH2 with HNO2 (Aliphatic)
 Aliphatic diazonium ions are unstable and lose N2
to give a carbocation which may:
1. Lose a proton to give an alkene.
2. React with a nucleophile to give a substitution
product.
3. Rearrange and then react by Steps 1 and/or 2.
Cl
(5.2%)
OH
N H2 N aN O2 , HCl + OH
0-5o C (13.2%) (25%)

+
(25.9%) (10.6%)
23-39
1° RNH2 with HNO2
 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

23-40
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)

:
:

:
:O H + O H proton transfer O
to H2O
+ CH2 CH2

A resonance-stabilized cation Cycloheptanone

Similar to pinacol rearrangement

23-41
Pinacol Rearrangement: an example of
stabilization of a carbocation by an adjacent
lone pair.

Overall:

23-42
Mechanism

Reversible
protonation.

Elimination
of water to This is a
yield tertiary protonated
carbocation. ketone!
1,2
rearrangement
to yield
resonance
stabilized
cation.
Deprotonation.

23-43
1° Primary Amines with HNO2 (Aromatic)

 The -N2+ group of an arenediazonium salt can be

replaced in a regioselective manner by these
groups.
H2 O
Ar-OH
HBF4 Schiemann
Ar-F
reaction
HCl, CuCl Ar-Cl
HNO2 + (-N2 ) Sandmeyer
Ar-NH2 Ar-N2 HBr, CuBr Ar-Br
0-5°C reaction
KCN, CuCN Ar-CN
KI
Ar-I
H3 PO2
Ar-H

23-44
1° ArNH2 with HNO2
 A 1° aromatic amine converted to a phenol.

NH2 OH
Br Br
1 . HNO2
2 . H2 O, he at
CH3 CH3
2-Bromo-4- 2-Bromo-4-
methylaniline methylphenol

23-45
1° ArNH2 with HNO2
Problem: What reagents and experimental conditions will
bring about this conversion?
CH3 CH3 COOH COOH COOH
(1) (2) (3) (4)

N O2 N O2 N H2 OH

23-46
1° ArNH2 with HNO2
 Problem: Show how to bring about each
conversion.
CH3
Cl

(5)
CH3 CH3 CH3
NH2 C N CH2 NH2
(7)
(6)

(8) CH3 CH3

NH2
(9)

Cl Cl Cl Cl

23-47
Hofmann Elimination
 Hofmann elimination: Thermal decomposition of
a quaternary ammonium hydroxide to give an
alkene.
• Step 1: Formation of a 4° ammonium hydroxide.
CH3 I-
+ H2 O
CH2 -N - CH 3 + Ag 2 O
CH3
(Cyclohexylmethyl)trimethyl- Silver
ammonium iodide oxide
CH3 OH-
+ + Ag I
CH2 -N - CH 3
CH3
(Cyclohexylmethyl)trimethyl-
ammonium hydroxide

23-48
Hofmann Elimination
• Step 2: Thermal decomposition of the 4° ammonium
hydroxide.
CH3 OH-
+ 160°
CH2 -N - CH 3
CH3
(Cyclohexylmethyl)trimethyl-
ammonium hydroxide

CH2 + ( CH3 ) 3 N + H2 O

Methylene- Trimethylamine
cyclohexane

23-49
Hofmann Elimination
 Hofmann elimination is regioselective - the major
product is the least substituted alkene.
CH3 heat
+ - CH2 + (CH3 ) 3 N + H2 O
N(CH3 ) 3 OH

 Hofmann’s rule: Any -elimination that occurs

preferentially to give the least substituted alkene
as the major product is said to follow Hofmann’s
rule.

23-50
Hofmann Elimination
HO -
H HOH
H H
E2 reaction H H
C C C C
H + (concerted CH3 CH 2 H
N ( CH3 ) 3 elimination)
CH3 CH 2 N ( CH3 ) 3

• The regioselectivity of Hofmann elimination is

determined largely by steric factors, namely the bulk
of the -NR3+ group.
• Hydroxide ion preferentially approaches and removes
the least hindered hydrogen and, thus, gives the least
substituted alkene.
• Bulky bases such as (CH3)3CO-K+ give largely Hofmann
elimination with haloalkanes.
23-51
Cope Elimination
 Cope elimination: Thermal decomposition of an
amine oxide.
Step 1: Oxidation of a 3° amine gives an amine oxide.
-
O
+
CH2 N-CH3 + H2 O2 CH2 N-CH3 + H2 O
CH3 CH3
An amine oxide

Step 2: If the amine oxide has at least one -hydrogen, it

undergoes thermal decomposition to give an alkene.
-
H O
+ 100-150°C
CH2 N-CH3 CH2 + (CH3 ) 2 NOH
CH3 N,N-Dimethyl-
Methylene-
cyclohexane hydroxylamine
23-52
Cope Elimination
• Cope elimination shows syn stereoselectivity but little
or no regioselectivity.
• Mechanism: a cyclic flow of electrons in a six-
membered transition state.
C C an alkene
C C CH3 heat
CH3
H N+ N,N-dimethyl-

:
- N
:O CH3 H hydroxylamine
O CH3
Transition state

23-53