Chapter 2

Amines
Amine Nomenclature
 Classification of Amines

Alkylamine
N attached to alkyl group
Arylamine
N attached to aryl group
Primary, secondary, or tertiary
determined by number of carbon atoms
directly attached to nitrogen
 Nomenclature of Primary Alkylamines (RNH2)

Two IUPAC styles

1) analogous to alcohols: replace -e
ending by -anamine
2) name alkyl group and attach -amine
as a suffix
 Examples: some primary alkylamines

(RNH2: one carbon directly attached to N)

CH3CH2NH2 ethylamine or ethanamine

NH2 cyclohexylamine or
cyclohexanamine

CH3CHCH2CH2CH3 1-methylbutylamine or
2-pentanamine
NH2
 Nomenclature of Primary Arylamines (ArNH2)

Name as derivatives of aniline.

NH2

F NH2 Br CH2CH3

p-fluoroaniline 5-bromo-2-ethylaniline
 Amino groups as substituents

amino groups rank below OH groups and higher

oxidation states of carbon
in such cases name the amino group as a
substituent

HOCH2CH2NH2 HC NH2

2-aminoethanol p-aminobenzaldehyde
 Secondary and Tertiary Amines

Name as N-substituted derivatives of parent

primary amine.
(N is a locant-it is not alphabetized, but
is treated the same way as a numerical
locant)
Parent amine is one with longest carbon
chain.
 Examples

CH3NHCH2CH3 N-methylethylamine
NHCH2CH3

4-chloro-N-ethyl-3-nitroaniline
NO2

Cl CH3
N
CH3
N,N-dimethylcycloheptylamine
 Ammonium Salts

A nitrogen with four substituents is positively

charged and is named as a derivative of
ammonium ion (NH4+).

CH3
+ – +
CH3NH3 Cl –
N CH2CH3 CF3CO2

methylammonium H
chloride N-ethyl-N-methylcyclopentylammonium
trifluoroacetate
 Ammonium Salts

When all four atoms attached to N are carbon,

the ion is called a quaternary ammonium ion and
salts that contain it are called quaternary
ammonium salts.
CH3
+ –
CH2 N CH3 I

CH3

benzyltrimethylammonium iodide
Structure and Bonding
Alkylamines

147 pm

112°
106°
 Alkylamines

Most prominent feature is high electrostatic

potential at nitrogen. Reactivity of nitrogen lone
pair dominates properties of amines.
 Geometry at N

Compare geometry at N of methylamine, aniline,

and formamide.
H H
H sp3 sp2
C NH2 C NH
O 2

H
Pyramidal geometry at sp3-hybridized N in
methylamine.
Planar geometry at sp2-hybridized N in
formamide.
 Geometry at N

Compare geometry at N of methylamine, aniline,

and formamide.

sp3 sp2

Pyramidal geometry at sp3-hybridized N in

methylamine.
Planar geometry at sp2-hybridized N in
formamide.
 Geometry at N

Angle that the C—N bond makes with bisector of

H—N—H angle is a measure of geometry at N.

sp3 sp2

180°
~125°

Note: this is not the same as the H—N—H

bond angle
 Geometry at N

Angle that the C—N bond makes with bisector of

H—N—H angle is a measure of geometry at N.

sp3 sp2

180°
~125°

142.5°
 Geometry at N

Geometry at N in aniline is pyramidal; closer to

methylamine than to formamide.

142.5°
 Geometry at N

Hybridization of N in aniline lies between sp3 and sp2.

Lone pair of N can be delocalized into ring best if N is
sp2 and lone pair is in a p orbital.
Lone pair bound most strongly by N if pair is in an sp3
orbital of N, rather than p.
Actual hybridization is a compromise that maximizes
binding of lone pair.

142.5°
 Electrostatic Potential Maps of Aniline

Nonplanar geometry at Planar geometry at N.

N. Region of highest High negative potential
negative potential is at N. shared by N and ring.

Figure 22.2 (page 947)

Physical Properties
 Physical Properties

Amines are more polar and have higher boiling

points than alkanes; but are less polar and
have lower boiling points than alcohols.

CH3CH2CH3 CH3CH2NH2 CH3CH2OH

dipole
moment (µ): 0D 1.2 D 1.7 D

boiling point: -42°C 17°C 78°C

 Physical Properties

CH3CH2CH2NH2 CH3CH2NHCH3 (CH3)3N

boiling 50°C 34°C 3°C
point:
Boiling points of isomeric amines decrease in
going from primary to secondary to tertiary amines.
Primary amines have two hydrogens on N capable
of being involved in intermolecular hydrogen
bonding. Secondary amines have one. Tertiary
amines cannot be involved in intermolecular
hydrogen bonds.
Basicity of Amines
 Effect of Structure on Basicity

1. Alkylamines are slightly stronger bases than

ammonia.
 Table 22.1 (page 950)
Basicity of Amines in Aqueous Solution

Amine Conj. Acid pKa

NH3 NH4+ 9.3

CH3CH2NH2 CH3CH2NH3+ 10.8

CH3CH2NH3+ is a weaker acid than NH4+;

therefore, CH3CH2NH2 is a stronger base
than NH3.
 Effect of Structure on Basicity

1. Alkylamines are slightly stronger bases than

ammonia.
2. Alkylamines differ very little in basicity.
 Table 22.1 (page 950)
Basicity of Amines in Aqueous Solution

Amine Conj. Acid pKa

NH3 NH4+ 9.3

CH3CH2NH2 CH3CH2NH3+ 10.8

(CH3CH2)2NH (CH3CH2)2NH2+ 11.1
(CH3CH2)3N (CH3CH2)3NH+ 10.8

Notice that the difference separating a primary,

secondary, and tertiary amine is only 0.3 pK units.
 Effect of Structure on Basicity

1. Alkylamines are slightly stronger bases than

ammonia.
2. Alkylamines differ very little in basicity.

3. Arylamines are much weaker bases than

ammonia.
 Table 22.1 (page 950)
Basicity of Amines in Aqueous Solution

Amine Conj. Acid pKa

NH3 NH4+ 9.3

CH3CH2NH2 CH3CH2NH3+ 10.8

(CH3CH2)2NH (CH3CH2)2NH2+ 11.1
(CH3CH2)3N (CH3CH2)3NH+ 10.8

C6H5NH2 C6H5NH3+ 4.6

 Decreased basicity of arylamines

H
+ ••
N H + H2N

Stronger H
pKa = 4.6 Stronger
acid base

•• +
NH2 + H3N
Weaker Weaker
base pKa =10.6
acid
 Decreased basicity of arylamines

H
+ ••
N H + H2N

Stronger H
acid When anilinium ion loses a proton, the
resulting lone pair is delocalized into the ring.

•• +
NH2 + H3N

Weaker
acid
 Decreased basicity of arylamines

H
+ ••
N H + H2N
H
Stronger
Aniline is a weaker base because its base
lone pair is more strongly held.

•• +
NH2 + H3N
Weaker
base
 Decreased basicity of arylamines

Increasing delocalization makes diphenylamine a

weaker base than aniline, and triphenylamine a
weaker base than diphenylamine.

C6H5NH2 (C6H5)2NH (C6H5)3N

pKa of conjugate acid:
4.6 0.8 ~-5
 Effect of Substituents on Basicity of Arylamines

1. Alkyl groups on the ring increase basicity, but

only slightly (less than 1 pK unit).

X NH2

X pKa of conjugate acid

H 4.6
CH3 5.3
 Effect of Substituents on Basicity of Arylamines

2. Electron withdrawing groups, especially ortho

and/or para to amine group, decrease basicity
and can have a large effect.

X NH2

X pKa of conjugate acid

H 4.6
CF3 3.5
O2N 1.0
 p-Nitroaniline

•• – ••
O •• •• O ••
+ •• + +
N NH2 N NH2
•• O •• •• O ••
– •• – ••
Lone pair on amine nitrogen is conjugated with
p-nitro group—more delocalized than in aniline
itself. Delocalization lost on protonation.
 Effect is Cumulative

Aniline is 3800 times more basic than

p-nitroaniline.
Aniline is ~1,000,000,000 times more basic than
2,4-dinitroaniline.
 Heterocyclic Amines

•• is more basic than

N N
••
H
piperidine pyridine
pKa of conjugate acid: pKa of conjugate acid:
11.2 5.2
(resembles an
(an alkylamine) arylamine in
basicity)
 Heterocyclic Amines

is more basic than

•• N •• N
H N
••

imidazole pyridine
pKa of conjugate acid: pKa of conjugate acid:
7.0 5.2
 Imidazole

Which nitrogen is protonated in imidazole?

•• N •• N
H

H+ H+

+ + H
•• N •• N N
H N H
H
 Imidazole

Protonation in the direction shown gives a

stabilized ion.
•• N •• N
H

H+

+ +
•• N N •• N H
H N H H
Tetraalkylammonium Salts
as Phase-Transfer Catalysts
 Phase-Transfer Catalysis

Phase-transfer agents promote the solubility of

ionic substances in nonpolar solvents. They
transfer the ionic substance from an aqueous
phase to a non-aqueous one.
Phase-transfer agents increase the rates of
reactions involving anions. The anion is relatively
unsolvated and very reactive in nonpolar media
compared to water or alcohols.
 Phase-Transfer Catalysis

Quaternary ammonium salts are phase-transfer

catalysts. They are soluble in nonpolar solvents.

CH2CH2CH2CH2CH2CH2CH2CH3
+
H3C N CH2CH2CH2CH2CH2CH2CH2CH3 Cl–

CH2CH2CH2CH2CH2CH2CH2CH3

Methyltrioctylammonium chloride
 Phase-Transfer Catalysis

Quaternary ammonium salts are phase-transfer

catalysts. They are soluble in nonpolar solvents.

CH2CH3
+
N CH2CH3 Cl–

CH2CH3

Benzyltriethylammonium chloride
 Example

The SN2 reaction of sodium cyanide with butyl

bromide occurs much faster when benzyl-
triethylammonium chloride is present than when
it is not.

CH3CH2CH2CH2Br + NaCN

benzyltriethylammonium chloride

CH3CH2CH2CH2CN + NaBr
 Mechanism
CH2CH3
+
N CH2CH3 Cl– + CN–
(aqueous)
CH2CH3
(aqueous)

CH2CH3
+
N CH2CH3 CN– + Cl–

CH2CH3 (aqueous)
(aqueous)
 Mechanism
CH2CH3
+
N CH2CH3 CN–

CH2CH3
(in butyl bromide)

CH2CH3
+
N CH2CH3 CN–

CH2CH3
(aqueous)
 Mechanism
CH2CH3
+
N CH2CH3 CN– + CH3CH2CH2CH2Br

CH2CH3
(in butyl bromide)

CH2CH3
+
N CH2CH3 Br– + CH3CH2CH2CH2CN

CH2CH3
(in butyl bromide)
 Reactions of Amines:
A Review and a Preview
 Preparation of Amines

Two questions to answer:

1) How is the C—N bond to be formed?
2) How do we obtain the correct oxidation
state of nitrogen (and carbon)?
 Methods for C—N Bond Formation

Nucleophilic substitution by azide ion (N3–) (Section 8.1, 8.11)

Nitration of arenes (Section 12.3)
Nucleophilic ring opening of epoxides by ammonia (Section
16.12)
Nucleophilic addition of amines to aldehydes and ketones
(Sections 17.10, 17.11)
Nucleophilic substitution by ammonia on α-halo acids
(Section 19.16)
Nucleophilic acyl substitution (Sections 20.4, 20.5, and
20.11)
 Preparation of Amines
by Alkylation of Ammonia
 Alkylation of Ammonia

Desired reaction is:

2 NH3 + R—X R—NH2 + NH4X

via:
•• + •• –
H3N •• + R X •• H3N R + •• X ••
•• ••
then: H H
+ +
H3N •• + H N R H3N H + •• N R

H H
 Alkylation of Ammonia

But the method doesn't work well in practice.

Usually gives a mixture of primary, secondary,
and tertiary amines, plus the quaternary salt.

RX RX
NH3 RNH2 R2NH

RX
+ – RX
R4N X R3N
 Example

NH3
CH3(CH2)6CH2Br CH3(CH2)6CH2NH2
(45%)
+
CH3(CH2)6CH2NHCH2(CH2)6CH3
(43%)
As octylamine is formed, it competes with
ammonia for the remaining 1-bromooctane.
Reaction of octylamine with 1-bromooctane
gives N,N-dioctylamine.
The Gabriel Synthesis of Primary Alkylamines
 Gabriel Synthesis

gives primary amines without formation of

secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form
the C—N bond
the nitrogen-containing nucleophile
is N-potassiophthalimide
 Gabriel Synthesis

gives primary amines without formation of

secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form
the C—N bond
the nitrogen-containing nucleophile
O
is N-potassiophthalimide
– +
•• N • K
•

O
 N-Potassiophthalimide

the pKa of phthalimide is 8.3

N-potassiophthalimide is easily prepared by
the reaction of phthalimide with KOH

O O
KOH – +
•• NH •• N • K
•

O O
N-Potassiophthalimide as a nucleophile

O O
– •• SN2
•• N • + R
• X •• •• N R
••

O O

•• –
+ •• X ••
••
 Cleavage of Alkylated Phthalimide

•• N R + H2O

O
imide hydrolysis is
acid or base nucleophilic acyl
substitution
CO2H
+ H2N R
CO2H
 Cleavage of Alkylated Phthalimide

hydrazinolysis is an alternative method of releasing

the amine from its phthalimide derivative

O O
H2NNH2 NH
•• N R
NH
O
O
+ H2N R
Example

O
– +
•• N •
• K + C6H5CH2Cl

O DMF

•• N CH2C6H5 (74%)

O
Example

NH
+ C6H5CH2NH2 (97%)
NH
H2NNH2
O
O

•• N CH2C6H5

O
Preparation of Amines by Reduction
 Preparation of Amines by Reduction

almost any nitrogen-containing compound can

be reduced to an amine, including:
azides
nitriles
nitro-substituted benzene derivatives
amides
 Synthesis of Amines via Azides

SN2 reaction, followed by reduction, gives a

primary alkylamine.
NaN3
CH2CH2Br CH2CH2N3

azides may also be (74%)

reduced by catalytic 1. LiAlH4
hydrogenation 2. H2O

CH2CH2NH2
(89%)
 Synthesis of Amines via Nitriles

SN2 reaction, followed by reduction, gives a

primary alkylamine.
NaCN
CH3CH2CH2CH2Br CH3CH2CH2CH2CN

nitriles may also be (69%)

reduced by lithium
H2 (100 atm), Ni
aluminum hydride

CH3CH2CH2CH2CH2NH2

(56%)
 Synthesis of Amines via Nitriles

SN2 reaction, followed by reduction, gives a

primary alkylamine.
NaCN
CH3CH2CH2CH2Br CH3CH2CH2CH2CN

the reduction also (69%)

works with cyanohydrins
H2 (100 atm), Ni

CH3CH2CH2CH2CH2NH2

(56%)
 Synthesis of Amines via Nitroarenes

HNO3
Cl Cl NO2
H2SO4
nitro groups may also (88-95%)
be reduced with tin (Sn)
+ HCl or by catalytic 1. Fe, HCl
hydrogenation
2. NaOH

Cl NH2

(95%)
 Synthesis of Amines via Amides

O O
1. SOCl2
COH CN(CH3)2
2. (CH3)2NH
(86-89%)
only LiAlH4 is an
appropriate reducing
agent for this reaction 1. LiAlH4
2. H2O

CH2N(CH3)2

(88%)
Reductive Amination
Synthesis of Amines via Reductive Amination

In reductive amination, an aldehyde or ketone

is subjected to catalytic hydrogenation in the
presence of ammonia or an amine.

R fast R
C O + NH3 C NH + H2O
R' R'

The aldehyde or ketone equilibrates with the

imine faster than hydrogenation occurs.
Synthesis of Amines via Reductive Amination

The imine undergoes hydrogenation faster

than the aldehyde or ketone. An amine is
the product.

R fast R
C O + NH3 C NH + H2O
R' R'
R
H2, Ni
R' C NH2

H
Example: Ammonia gives a primary amine.

H2, Ni H
O + NH3
ethanol NH2

(80%)

via: NH
Example: Primary amines give secondary amines

O
CH3(CH2)5CH + H2N

H2, Ni ethanol

CH3(CH2)5CH2NH (65%)

via: CH3(CH2)5CH N
Example: Secondary amines give tertiary amines

CH3CH2CH2CH +
N

H
H2, Ni, ethanol

CH2CH2CH2CH3 (93%)
 Example: Secondary amines give tertiary amines

possible intermediates include:

+
N N

HO CHCH2CH2CH3 CHCH2CH2CH3

CH CHCH2CH3
 Friedel-Crafts Reactions

The amino group of an arylamine must be

protected as an amide when carrying out a
Friedel-Crafts reaction.
O O

NHCCH3 O NHCCH3

CH2CH3 CH3
CH3CCl
AlCl3

O CCH3 (57%)
Nitrosation of Alkylamines
 Nitrite Ion, Nitrous Acid, and Nitrosyl Cation

+
– •• •• •
H •• •• •
•• O •• ••
N O• H O N O•
•• ••
+
H

H H
•• •• • + •• •• •
•• O •• + N O• •• O N O•
+
H H
Nitrosyl Cation and Nitrosation

•• •• •
N O•
+
 Nitrosyl Cation and Nitrosation

+ •• •• •
N N O•

N •• + •• •• •
N O•
+
 Nitrosation of Secondary Alkylamines

+ •• •• • •• •• •
N N O• •• N N O•

H +
+
H

N •• + •• •• • nitrosation of
N O•
+ secondary amines
gives an N-nitroso
H amine
 Example

•• NaNO2, HCl •• •• •• •
(CH3)2NH (CH3)2N N O•
H2O
(88-90%)
 Some N-Nitroso Amines

N-nitrosodimethylamine
(CH3)2N N O
(leather tanning)

N N

N N
N
O O

N-nitrosopyrrolidine N-nitrosonornicotine
(nitrite-cured bacon) (tobacco smoke)
 Nitrosation of Primary Alkylamines

R R
H + •• •• • •• •• •
N N O• •• N N O•

H H +
+
R H
H
N •• + •• •• • analogous to
N O•
+ nitrosation of
secondary amines
H to this point
 Nitrosation of Primary Alkylamines

R R
+
•• •• + H •• •• •
•• N N O •• N N O•

H H H
this species reacts further
R R H
+
•• •• • H ••
•• N N O• •• N N O ••
+
+ H H
H
 Nitrosation of Primary Alkylamines

nitrosation of a H
+
primary alkylamine + •• O ••
R N N ••
gives an alkyl
diazonium ion H
process is called
diazotization R H
••
•• N N O ••
+
H
 Alkyl Diazonium Ions

+
+ + •N N N ••
R • N •• R

alkyl diazonium ions

readily lose N2 to
give carbocations
 Example: Nitrosation of 1,1-Dimethylpropylamine

+
NH2 HONO N N

OH H2O – N2
+

(80%)
+

Mechanism 77 pg. 973 (3%) (2%)

 Nitrosation of Tertiary Alkylamines

There is no useful chemistry associated with the

nitrosation of tertiary alkylamines.

R R
R R + •• •• •
N •• N N O•

R R
Nitrosation of Arylamines
 Nitrosation of Tertiary Arylamines

reaction that occurs is

electrophilic aromatic substitution

N(CH2CH3)2 N(CH2CH3)2
1. NaNO2, HCl,
H2O, 8°C
2. HO–

N
O
(95%)
Nitrosation of N-Alkylarylamines

similar to secondary alkylamines;

gives N-nitroso amines

NaNO2, HCl, N O
H2O, 10°C
NHCH3 NCH3

(87-93%)
 Nitrosation of Primary Arylamines

gives aryl diazonium ions

aryl diazonium ions are much more stable than
alkyl diazonium ions
most aryl diazonium ions are stable under the
conditions of their formation (0-10°C)
+ fast +
RN N R + N2

+ slow +
ArN N Ar + N2
Example:

(CH3)2CH NH2

NaNO2, H2SO4
H2O, 0-5°C

+
(CH3)2CH N N HSO4–
Synthetic Origin of Aryl Diazonium Salts

Ar H

Ar NO2

Ar NH2

+
Ar N N
Synthetic Transformations
of Aryl Diazonium Salts
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
Preparation of Phenols

+
Ar N N

H2O, heat

Ar OH
Example

(CH3)2CH NH2

1. NaNO2, H2SO4
H2O, 0-5°C
2. H2O, heat

(CH3)2CH OH

(73%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Preparation of Aryl Iodides

reaction of an aryl diazonium salt with

potassium iodide

+
Ar N N
KI
Ar I
Example

NH2 I
1. NaNO2, HCl
Br H2O, 0-5°C Br

2. KI, room temp.

(72-83%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Preparation of Aryl Fluorides

Ar F
+
Ar N N

heat the tetrafluoroborate salt of a diazonium ion;

process is called the Schiemann reaction
 Example

NH2 1. NaNO2, HCl, F

H2O, 0-5°C

2. HBF4
CCH2CH3 CCH2CH3
3. heat
O O
(68%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Preparation of Aryl Chlorides and Bromides

Ar Cl Ar Br

+
Ar N N

aryl chlorides and aryl bromides are prepared by

heating a diazonium salt with copper(I) chloride or
bromide
substitutions of diazonium salts that use copper(I)
halides are called Sandmeyer reactions
 Example

NH2 1. NaNO2, HCl, Cl

H2O, 0-5°C

2. CuCl, heat
NO2 NO2

(68-71%)
 Example

NH2 1. NaNO2, HBr, Br

H2O, 0-10°C
Cl Cl

2. CuBr, heat

(89-95%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Preparation of Aryl Nitriles

Ar CN
+
Ar N N

aryl nitriles are prepared by heating a diazonium

salt with copper(I) cyanide
this is another type of Sandmeyer reaction
 Example

NH2 1. NaNO2, HCl, CN

H2O, 0°C
CH3 CH3

2. CuCN, heat

(64-70%)
 Transformations of Aryl Diazonium Salts

Ar Cl Ar Br

Ar CN Ar F
+
Ar N N

Ar H Ar I

Ar OH
 Transformations of Aryl Diazonium Salts

hypophosphorous acid (H3PO2) reduces diazonium

salts; ethanol does the same thing
this is called reductive deamination
+
Ar N N

Ar H
 Example

NH2 NaNO2, H2SO4,

H3PO2
CH3 CH3

(70-75%)
 Value of Diazonium Salts

1) allows introduction of substituents such as

OH, F, I, and CN on the ring
2) allows preparation of otherwise difficultly
accessible substitution patterns
 Example

NH2 NH2
NaNO2, H2SO4,
Br Br
Br2 H2O, CH3CH2OH
H2O

Br Br
Br
(100%)

Br
(74-77%)
Azo Coupling
 Azo Coupling

Diazonium salts are weak electrophiles.

React with strongly activated aromatic
compounds by electrophilic aromatic
substitution.
+
Ar N N + Ar' H Ar N N Ar'

an azo compound

Ar' must bear a strongly electron-releasing group

such as OH, OR, or NR2.
Example
OH

+
+ C6H5N N Cl–

OH

N NC6H5