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Chapter 21

Amines

Dr. Wolf's CHM 201 & 202

21-1

Amine Nomenclature

Dr. Wolf's CHM 201 & 202

21-2

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
Dr. Wolf's CHM 201 & 202

21-3

Nomenclature of Primary Alkylamines (RNH2)


Two IUPAC styles
1)

analogous to alcohols: replace -e


ending by -amine

2)

name alkyl group and attach -amine


as a suffix

Dr. Wolf's CHM 201 & 202

21-4

Examples: some primary alkylamines


(RNH2: one carbon directly attached to N)
CH3CH2NH2

ethylamine or ethanamine
NH2

CH3CHCH2CH2CH3
NH2
Dr. Wolf's CHM 201 & 202

cyclohexylamine or
cyclohexanamine
1-methylbutylamine or
2-pentanamine
21-5

Nomenclature of Primary Arylamines (ArNH2)


Name as derivatives of aniline.

NH2

NH2

p-fluoroaniline

Dr. Wolf's CHM 201 & 202

Br

CH2CH3

5-bromo-2-ethylaniline

21-6

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

O
HOCH2CH2NH2

HC

2-aminoethanol

p-aminobenzaldehyde

Dr. Wolf's CHM 201 & 202

NH2

21-7

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.

Dr. Wolf's CHM 201 & 202

21-8

Examples
CH3NHCH2CH3

N-methylethylamine

NHCH2CH3
4-chloro-N-ethyl-3-nitroaniline
NO2
Cl

Dr. Wolf's CHM 201 & 202

CH3
N

CH3

N,N-dimethylcycloheptylamine
21-9

Ammonium Salts
A nitrogen with four substituents is positively
charged and is named as a derivative of
ammonium ion (NH4+).
+
CH3NH3 Cl
methylammonium
chloride

Dr. Wolf's CHM 201 & 202

CH3
+

CF
CO
CH
CH
N
3
2
2
3
H

N-ethyl-N-methylcyclopentylammonium
trifluoroacetate
21-10

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

CH3
benzyltrimethylammonium iodide
Dr. Wolf's CHM 201 & 202

21-11

Structure and Bonding

Dr. Wolf's CHM 201 & 202

21-12

Alkylamines
147 pm

112

Dr. Wolf's CHM 201 & 202

106

21-13

Alkylamines

Most prominent feature is high electrostatic


potential at nitrogen. Reactivity of nitrogen lone
pair dominates properties of amines.
Dr. Wolf's CHM 201 & 202

21-14

Geometry at N
Compare geometry at N of methylamine, aniline,
and formamide.
H
H
H
sp3
sp2
NH2
NH2
C
C
O
H
Pyramidal geometry at sp3-hybridized N in
methylamine.
Planar geometry at sp2-hybridized N in formamide.
Dr. Wolf's CHM 201 & 202

21-15

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.
Dr. Wolf's CHM 201 & 202

21-16

Geometry at N
Angle that the CN bond makes with bisector of
HNH angle is a measure of geometry at N.
sp3

~125

sp2
180

Note: this is not the same as the HNH bond angle

Dr. Wolf's CHM 201 & 202

21-17

Geometry at N
Angle that the CN bond makes with bisector of
HNH angle is a measure of geometry at N.
sp3

sp2
180

~125

142.5
Dr. Wolf's CHM 201 & 202

21-18

Geometry at N
Geometry at N in aniline is pyramidal; closer to
methylamine than to formamide.

142.5
Dr. Wolf's CHM 201 & 202

21-19

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
Dr. Wolf's CHM 201 & 202

21-20

Electrostatic Potential Maps of Aniline

Nonplanar geometry at
N. Region of highest
negative potential is at N.

Dr. Wolf's CHM 201 & 202

Planar geometry at N.
High negative potential
shared by N and ring.

21-21

Physical Properties

Dr. Wolf's CHM 201 & 202

21-22

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 ():

0D

1.2 D

1.7 D

boiling point:

-42C

17C

78C

Dr. Wolf's CHM 201 & 202

21-23

Physical Properties
CH3CH2CH2NH2
boiling
point:

50C

CH3CH2NHCH3
34C

(CH3)3N
3C

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.
Dr. Wolf's CHM 201 & 202

21-24

Basicity of Amines

Dr. Wolf's CHM 201 & 202

21-25

Effect of Structure on Basicity

1. Alkylamines are slightly stronger bases than


ammonia.

Dr. Wolf's CHM 201 & 202

21-26

Table 22.1 (page 920)


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.
Dr. Wolf's CHM 201 & 202

21-27

Effect of Structure on Basicity

1. Alkylamines are slightly stronger bases than


ammonia.
2. Alkylamines differ very little in basicity.

Dr. Wolf's CHM 201 & 202

21-28

Table 22.1 (page 920)


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.
Dr. Wolf's CHM 201 & 202

21-29

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.

Dr. Wolf's CHM 201 & 202

21-30

Table 22.1 (page 920)


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

Dr. Wolf's CHM 201 & 202

21-31

Decreased basicity of arylamines

H
+
N

Stronger pKa = 4.6


acid

H + H2N

NH2 +

Dr. Wolf's CHM 201 & 202

Stronger
base

Weaker
base

+
H3N
pKa =10.6

Weaker
acid
21-32

Decreased basicity of arylamines

H
+
N

H + H2N

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

NH2 +

+
H3N
Weaker
acid

Dr. Wolf's CHM 201 & 202

21-33

Decreased basicity of arylamines

H
+
N

H + H2N

H
Aniline is a weaker base because its
lone pair is more strongly held.

Stronger
base

NH2 +

+
H3N

Weaker
base
Dr. Wolf's CHM 201 & 202

21-34

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

0.8

~-5

pKa of conjugate acid:


4.6

Dr. Wolf's CHM 201 & 202

21-35

Effect of Substituents on Basicity of Arylamines


1. Alkyl groups on the ring increase basicity, but
only slightly (less than 1 pK unit).

X
X
H
CH3
Dr. Wolf's CHM 201 & 202

NH2
pKa of conjugate acid
4.6
5.3
21-36

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
X
H
CF3
O2N
Dr. Wolf's CHM 201 & 202

NH2
pKa of conjugate acid
4.6
3.5
1.0
21-37

p-Nitroaniline

+
N

NH2


O
+
N

+
NH2

Lone pair on amine nitrogen is conjugated with


p-nitro groupmore delocalized than in aniline
itself. Delocalization lost on protonation.
Dr. Wolf's CHM 201 & 202

21-38

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.

Dr. Wolf's CHM 201 & 202

21-39

Heterocyclic Amines

is more basic than

H
piperidine
pKa of conjugate acid:
11.2
(an alkylamine)
Dr. Wolf's CHM 201 & 202

pyridine
pKa of conjugate acid:
5.2
(resembles an
arylamine in
basicity)

21-40

Heterocyclic Amines

is more basic than

imidazole
pKa of conjugate acid:
7.0

Dr. Wolf's CHM 201 & 202

pyridine
pKa of conjugate acid:
5.2

21-41

Imidazole
Which nitrogen is protonated in imidazole?

H+

H+

+
H N
Dr. Wolf's CHM 201 & 202

+ H
N
H

21-42

Imidazole
Protonation in the direction shown gives a

stabilized ion.
N

H+

+
H N
Dr. Wolf's CHM 201 & 202

+
N H
21-43

Tetraalkylammonium Salts
as Phase-Transfer Catalysts

Dr. Wolf's CHM 201 & 202

21-44

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.

Dr. Wolf's CHM 201 & 202

21-45

Phase-Transfer Catalysis
Quaternary ammonium salts are phase-transfer
catalysts. They are soluble in nonpolar solvents.
CH2CH2CH2CH2CH2CH2CH2CH3
H3C

+
N CH2CH2CH2CH2CH2CH2CH2CH3

Cl

CH2CH2CH2CH2CH2CH2CH2CH3
Methyltrioctylammonium chloride
Dr. Wolf's CHM 201 & 202

21-46

Phase-Transfer Catalysis
Quaternary ammonium salts are phase-transfer
catalysts. They are soluble in nonpolar solvents.
CH2CH3

+
N CH2CH3

Cl

CH2CH3
Benzyltriethylammonium chloride
Dr. Wolf's CHM 201 & 202

21-47

Example
The SN2 reaction of sodium cyanide with butyl
bromide occurs much faster when benzyltriethylammonium chloride is present than when
it is not.
CH3CH2CH2CH2Br +

NaCN
benzyltriethylammonium chloride

CH3CH2CH2CH2CN
Dr. Wolf's CHM 201 & 202

NaBr
21-48

Mechanism
Mechanism

CH2CH3
+
N CH2CH3 Cl
CH2CH3

CN

(aqueous)

(aqueous)

CH2CH3
+
N CH2CH3 CN
CH2CH3

(aqueous)
Dr. Wolf's CHM 201 & 202

Cl

(aqueous)
21-49

CH2CH3

Mechanism
Mechanism

+
N CH2CH3 CN
CH2CH3
(in butyl bromide)

CH2CH3
+
N CH2CH3 CN
CH2CH3

(aqueous)
Dr. Wolf's CHM 201 & 202

21-50

CH2CH3

Mechanism
Mechanism

+
N CH2CH3 CN + CH3CH2CH2CH2Br
CH2CH3
(in butyl bromide)

CH2CH3
+
N CH2CH3 Br + CH3CH2CH2CH2CN

CH2CH3
(in butyl bromide)
Dr. Wolf's CHM 201 & 202

21-51

Reactions of Amines:
A Review and a Preview

Dr. Wolf's CHM 201 & 202

21-52

Preparation of Amines

Two questions to answer:


1) How is the CN bond to be formed?
2) How do we obtain the correct oxidation
state of nitrogen (and carbon)?

Dr. Wolf's CHM 201 & 202

21-53

Methods for CN Bond Formation


Nucleophilic substitution by azide ion (N3) (Section 8.1, 8.13)
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 acyl substitution (Sections 19.4, 19.5, and 19.11)
Nucleophilic substitution by ammonia on -halo acids
(Section 20.15)
Dr. Wolf's CHM 201 & 202

21-54

Preparation of Amines
by Alkylation of Ammonia

Dr. Wolf's CHM 201 & 202

21-55

Alkylation of Ammonia
Desired reaction is:
2 NH3

+ RX

RNH2 +

NH4X

+
H3N

via:
H3N + R
then:
H3N + H
Dr. Wolf's CHM 201 & 202

H
+
N R
H

R +

H
+
H3N

H + N
H

R
21-56

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.

NH3

RX

RNH2

RX

R2NH
RX

+
R4N
X
Dr. Wolf's CHM 201 & 202

RX

R3N
21-57

Example
CH3(CH2)6CH2Br

NH3

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.
Dr. Wolf's CHM 201 & 202

21-58

The Gabriel Synthesis of


Primary Alkylamines

Dr. Wolf's CHM 201 & 202

21-59

Gabriel Synthesis
gives primary amines without formation of
secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form
the CN bond
the nitrogen-containing nucleophile
is N-potassiophthalimide

Dr. Wolf's CHM 201 & 202

21-60

Gabriel Synthesis
gives primary amines without formation of
secondary, etc. amines as byproducts
uses an SN2 reaction on an alkyl halide to form
the CN bond
the nitrogen-containing nucleophile

is N-potassiophthalimide

O
Dr. Wolf's CHM 201 & 202

21-61

N-Potassiophthalimide
the pKa of phthalimide is 8.3
N-potassiophthalimide is easily prepared by
the reaction of phthalimide with KOH

NH

O
Dr. Wolf's CHM 201 & 202

O
KOH

O
21-62

N-Potassiophthalimide as a nucleophile

+ R

SN2

O
+

Dr. Wolf's CHM 201 & 202

21-63

Cleavage of Alkylated Phthalimide

O
N

R + H2O

imide hydrolysis is
nucleophilic acyl
substitution

acid or base

CO2H
+

H2N

CO2H
Dr. Wolf's CHM 201 & 202

21-64

Cleavage of Alkylated Phthalimide


hydrazinolysis is an alternative method of releasing the
amine from its phthalimide derivative

O
N

H2NNH2

NH
NH

O
+

Dr. Wolf's CHM 201 & 202

H2N

R
21-65

Example

C6H5CH2Cl
DMF

O
N

CH2C6H5

(74%)

O
Dr. Wolf's CHM 201 & 202

21-66

Example

O
NH

NH

H2NNH2

C6H5CH2NH2 (97%)

O
N

CH2C6H5

O
Dr. Wolf's CHM 201 & 202

21-67

Preparation of Amines by
Reduction

Dr. Wolf's CHM 201 & 202

21-68

Preparation of Amines by Reduction


almost any nitrogen-containing compound can
be reduced to an amine, including:
azides
nitriles
nitro-substituted benzene derivatives
amides

Dr. Wolf's CHM 201 & 202

21-69

Synthesis of Amines via Azides

SN2 reaction, followed by reduction, gives a


primary alkylamine.

CH2CH2Br

NaN3

CH2CH2N3
(74%)
1. LiAlH4
2. H2O

azides may also be


reduced by catalytic
hydrogenation

CH2CH2NH2
(89%)
Dr. Wolf's CHM 201 & 202

21-70

Synthesis of Amines via Nitriles


SN2 reaction, followed by reduction, gives a
primary alkylamine.

CH3CH2CH2CH2Br
nitriles may also be
reduced by lithium
aluminum hydride

NaCN

CH3CH2CH2CH2CN
(69%)
H2 (100 atm), Ni

CH3CH2CH2CH2CH2NH2
(56%)
Dr. Wolf's CHM 201 & 202

21-71

Synthesis of Amines via Nitriles


SN2 reaction, followed by reduction, gives a
primary alkylamine.

CH3CH2CH2CH2Br

NaCN

the reduction also


works with cyanohydrins

CH3CH2CH2CH2CN
(69%)
H2 (100 atm), Ni

CH3CH2CH2CH2CH2NH2
(56%)
Dr. Wolf's CHM 201 & 202

21-72

Synthesis of Amines via Nitroarenes

HNO3

Cl

H2SO4

nitro groups may also


be reduced with tin (Sn)
+ HCl or by catalytic
hydrogenation

(88-95%)
1. Fe, HCl
2. NaOH

Cl

NH2
(95%)

Dr. Wolf's CHM 201 & 202

NO2

Cl

21-73

Synthesis of Amines via Amides


O

COH

1. SOCl2

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%)
Dr. Wolf's CHM 201 & 202

21-74

Reductive Amination

Dr. Wolf's CHM 201 & 202

21-75

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
C

R'

O + NH3

NH + H2O

R'

The aldehyde or ketone equilibrates with the


imine faster than hydrogenation occurs.
Dr. Wolf's CHM 201 & 202

21-76

Synthesis of Amines via Reductive Amination


The imine undergoes hydrogenation faster
than the aldehyde or ketone. An amine is
the product.
R

fast

O + NH3

C
R'

Dr. Wolf's CHM 201 & 202

C
H

NH + H2O

R'

R
R'

H2, Ni
NH2
21-77

Example: Ammonia gives a primary amine.

H2, Ni

O + NH3

H
NH2

ethanol
(80%)

via:

Dr. Wolf's CHM 201 & 202

NH
21-78

Example: Primary amines give secondary amines


O
CH3(CH2)5CH

+ H2N

H2, Ni

ethanol

CH3(CH2)5CH2NH

(65%)

via:
Dr. Wolf's CHM 201 & 202

CH3(CH2)5CH

N
21-79

Example: Secondary amines give tertiary amines

O
CH3CH2CH2CH

N
H

H2, Ni, ethanol

N
CH2CH2CH2CH3
Dr. Wolf's CHM 201 & 202

(93%)

21-80

Example: Secondary amines give tertiary amines


possible intermediates include:

+
N

N
HO

CHCH2CH2CH3

CHCH2CH2CH3

N
CH
Dr. Wolf's CHM 201 & 202

CHCH2CH3

21-81

Reactions of Amines:
A Review and a Preview

Dr. Wolf's CHM 201 & 202

21-82

Reactions of Amines
Reactions of amines almost always involve the
nitrogen lone pair.

as a base:

as a nucleophile:
Dr. Wolf's CHM 201 & 202

21-83

Reactions of Amines
Reactions already discussed
basicity (Section 21.4)
reaction with aldehydes and ketones (Chapter 17)
reaction with acyl chlorides,
anhydrides, and esters

Dr. Wolf's CHM 201 & 202

21-84

Reactions of Amines with Alkyl


Halides

Dr. Wolf's CHM 201 & 202

21-85

Reaction with Alkyl Halides


Amines act as nucleophiles toward alkyl halides.

N + R

Dr. Wolf's CHM 201 & 202

N R + X

+
21-86

Example: excess amine

NH2

ClCH2

(4 mol)

(1 mol)

NaHCO3

90C

NHCH2
(85-87%)
Dr. Wolf's CHM 201 & 202

21-87

Example: excess alkyl halide

CH2NH2

methanol

3CH3I

heat

+
CH2N (CH3)3 I
(99%)

Dr. Wolf's CHM 201 & 202

21-88

The Hofmann Elimination

Dr. Wolf's CHM 201 & 202

21-89

The Hofmann Elimination


a quaternary ammonium hydroxide is the reactant
and an alkene is the product
is an anti elimination
the leaving group is a trialkylamine
the regioselectivity is opposite to the Zaitsev rule.

Dr. Wolf's CHM 201 & 202

21-90

Quaternary Ammonium Hydroxides


are prepared by treating quaternary ammmonium
halides with moist silver oxide

CH2N (CH3)3 I
Ag2O

Dr. Wolf's CHM 201 & 202

H2O, CH3OH

+
CH2N (CH3)3 HO
21-91

The Hofmann Elimination


on being heated, quaternary ammonium
hydroxides undergo elimination

CH2 +

N(CH3)3

+ H2O

(69%)
160C

Dr. Wolf's CHM 201 & 202

+
CH2N (CH3)3 HO
21-92

Mechanism

CH2

CH2
N(CH3)3
+
N(CH3)3

Dr. Wolf's CHM 201 & 202

21-93

Regioselectivity
Elimination occurs in the direction that gives
the less-substituted double bond. This is called
the Hofmann rule.
H2C

CH3CHCH2CH3
+ N(CH3)3

HO

Dr. Wolf's CHM 201 & 202

CHCH2CH3 (95%)

heat

+
CH3CH

CHCH3 (5%)

21-94

Regioselectivity
Steric factors seem to control the regioselectivity.
The transition state that leads to 1-butene is
less crowded than the one leading to cis
or trans-2-butene.

Dr. Wolf's CHM 201 & 202

21-95

Regioselectivity

CH3CH2

CH3CH2

+ N(CH3)3

C
C

major product

largest group is between two H atoms

Dr. Wolf's CHM 201 & 202

21-96

Regioselectivity

CH3

H
CH3

H
+ N(CH3)3

CH3

C
C

CH3

minor product

largest group is between an


H atom and a methyl group
Dr. Wolf's CHM 201 & 202

21-97

Electrophilic Aromatic
Substitution
in Arylamines

Dr. Wolf's CHM 201 & 202

21-98

Nitration of Anililne

NH2 is a very strongly activating group


NH2 not only activates the ring toward
electrophilic aromatic substitution, it also
makes it more easily oxidized
attemped nitration of aniline fails because
nitric acid oxidizes aniline to a black tar

Dr. Wolf's CHM 201 & 202

21-99

Nitration of Anililne
Strategy: decrease the reactivity of aniline by
converting the NH2 group to an amide
O

NH2

O O
CH3COCCH3

CH(CH3)2

NHCCH3
(98%)

CH(CH3)2

(acetyl chloride may be used instead of acetic anhydride)


Dr. Wolf's CHM 201 & 202

21-100

Nitration of Anililne
Strategy: nitrate the amide formed in the first
step
O
O

NHCCH3
NO2

CH(CH3)2

NHCCH3

HNO3

CH(CH3)2

(94%)
Dr. Wolf's CHM 201 & 202

21-101

Nitration of Anililne
Strategy: remove the acyl group from the amide
by hydrolysis
O

NHCCH3
NO2

CH(CH3)2

NH2
NO2

KOH
ethanol,
heat

CH(CH3)2
(100%)

Dr. Wolf's CHM 201 & 202

21-102

Halogenation of Arylamines
occurs readily without necessity of protecting
amino group, but difficult to limit it to
monohalogenation

NH2
NH2

Br2

Br

Br

acetic acid
CO2H
Dr. Wolf's CHM 201 & 202

CO2H
(82%)

21-103

Monohalogenation of Arylamines
Decreasing the reactivity of the arylamine by
converting the NH2 group to an amide allows
halogenation to be limited to monosubstitution

NHCCH3
CH3

NHCCH3
CH3

Cl2
acetic acid

Dr. Wolf's CHM 201 & 202

Cl

(74%)
21-104

Friedel-Crafts Reactions
The amino group of an arylamine must be protected
as an amide when carrying out a Friedel-Crafts
reaction.

NHCCH3
CH3

NHCCH3
CH3

CH3CCl
AlCl3
O

Dr. Wolf's CHM 201 & 202

CCH3 (57%)
21-105

Nitrosation of Alkylamines

Dr. Wolf's CHM 201 & 202

21-106

Nitrite Ion, Nitrous Acid, and Nitrosyl Cation

+
H

N
H

H
O

H
Dr. Wolf's CHM 201 & 202

N
+

+
O

H
21-107

Nitrosyl Cation and Nitrosation

N
+

Dr. Wolf's CHM 201 & 202

21-108

Nitrosyl Cation and Nitrosation


+
N

Dr. Wolf's CHM 201 & 202

N
+

21-109

Nitrosation of Secondary Alkylamines


+

N
+

H
Dr. Wolf's CHM 201 & 202

N
+

nitrosation of secondary
amines gives an Nnitroso amine
21-110

Example

(CH3)2NH

Dr. Wolf's CHM 201 & 202

NaNO2, HCl
H2O

(CH3)2N

(88-90%)

21-111

Some N-Nitroso Amines

(CH3)2N

N-nitrosodimethylamine
(leather tanning)

N-nitrosopyrrolidine
(nitrite-cured bacon)
Dr. Wolf's CHM 201 & 202

N-nitrosonornicotine
(tobacco smoke)
21-112

Nitrosation of Primary Alkylamines


R

H
H

N
+
H

H
Dr. Wolf's CHM 201 & 202

N
+

analogous to
nitrosation of
secondary amines to
this point
21-113

Nitrosation of Primary Alkylamines


R

H
R
N

Dr. Wolf's CHM 201 & 202

H
this species reacts further
R
H
N

O
+
H
21-114

Nitrosation of Primary Alkylamines

nitrosation of a
primary alkylamine
gives an alkyl
diazonium ion
process is called
diazotization

H
R

+
N

H
R

Dr. Wolf's CHM 201 & 202

O
+
H
21-115

Alkyl Diazonium Ions

+ +
R
N

+
N

alkyl diazonium ions


readily lose N2 to
give carbocations
Dr. Wolf's CHM 201 & 202

21-116

Example: Nitrosation of 1,1-Dimethylpropylamine

+
N

HONO

NH2

OH
(80%)

H2O

N2

+
(3%)
Dr. Wolf's CHM 201 & 202

(2%)
21-117

Nitrosation of Tertiary Alkylamines


There is no useful chemistry associated with the
nitrosation of tertiary alkylamines.
R
R

N
R

Dr. Wolf's CHM 201 & 202

R
R

+
N

21-118

Nitrosation of Arylamines

Dr. Wolf's CHM 201 & 202

21-119

Nitrosation of Tertiary Arylamines


reaction that occurs is
electrophilic aromatic substitution

N(CH2CH3)2

1. NaNO2, HCl,
H2O, 8C

N(CH2CH3)2

2. HO
N

(95%)
Dr. Wolf's CHM 201 & 202

21-120

Nitrosation of N-Alkylarylamines
similar to secondary alkylamines;
gives N-nitroso amines

NHCH3

NaNO2, HCl,
H2O, 10C

NCH3
(87-93%)

Dr. Wolf's CHM 201 & 202

21-121

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 (0-10C)
+
RN
+
ArN
Dr. Wolf's CHM 201 & 202

N
N

fast

+
R

+ N2

slow

+
Ar

+ N2
21-122

Example:

(CH3)2CH

NH2
NaNO2, H2SO4
H2O, 0-5C

(CH3)2CH
Dr. Wolf's CHM 201 & 202

+
N

N HSO4
21-123

Synthetic Origin of Aryl Diazonium Salts


Ar

H
Ar

NO2
Ar

NH2

Ar
Dr. Wolf's CHM 201 & 202

+
N

N
21-124

Synthetic Transformations
of Aryl Diazonium Salts

Dr. Wolf's CHM 201 & 202

21-125

Transformations of Aryl Diazonium Salts


Ar
Ar

Cl

Ar

CN
+
N

Ar
Ar

Dr. Wolf's CHM 201 & 202

Ar

Ar

H
Ar

Br

OH
21-126

Preparation of Phenols

+
N

Ar

N
H2O, heat

Ar
Dr. Wolf's CHM 201 & 202

OH
21-127

Example

NH2

(CH3)2CH

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

OH

(CH3)2CH
(73%)
Dr. Wolf's CHM 201 & 202

21-128

Transformations of Aryl Diazonium Salts


Ar
Ar

Cl

Ar

CN
+
N

Ar
Ar

Dr. Wolf's CHM 201 & 202

Ar

Ar

H
Ar

Br

OH
21-129

Preparation of Aryl Iodides


reaction of an aryl diazonium salt with
potassium iodide

Ar

+
N

KI
Ar

Dr. Wolf's CHM 201 & 202

21-130

Example

NH2
Br

1. NaNO2, HCl
H2O, 0-5C

I
Br

2. KI, room temp.


(72-83%)

Dr. Wolf's CHM 201 & 202

21-131

Transformations of Aryl Diazonium Salts


Ar
Ar

Cl

Ar

CN
+
N

Ar
Ar

Dr. Wolf's CHM 201 & 202

Ar

Ar

H
Ar

Br

OH
21-132

Preparation of Aryl Fluorides

Ar
Ar

+
N

heat the tetrafluoroborate salt of a diazonium ion;


process is called the Schiemann reaction

Dr. Wolf's CHM 201 & 202

21-133

Example

NH2

1. NaNO2, HCl,

H2O, 0-5C
CCH2CH3
O

2. HBF4
3. heat

CCH2CH3
O
(68%)

Dr. Wolf's CHM 201 & 202

21-134

Transformations of Aryl Diazonium Salts


Ar
Ar

Cl

Ar

CN
+
N

Ar
Ar

Dr. Wolf's CHM 201 & 202

Ar

Ar

H
Ar

Br

OH
21-135

Preparation of Aryl Chlorides and


Bromides
Ar

Cl

Ar

Ar
+
N

Br

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
Dr. Wolf's CHM 201 & 202

21-136

Example

NH2

1. NaNO2, HCl,

Cl

H2O, 0-5C
NO2

2. CuCl, heat

NO2
(68-71%)

Dr. Wolf's CHM 201 & 202

21-137

Example

1. NaNO2, HBr,

NH2
Cl

H2O, 0-10C

Br
Cl

2. CuBr, heat
(89-95%)

Dr. Wolf's CHM 201 & 202

21-138

Transformations of Aryl Diazonium Salts


Ar
Ar

Cl

Ar

CN
+
N

Ar
Ar

Dr. Wolf's CHM 201 & 202

Ar

Ar

H
Ar

Br

OH
21-139

Preparation of Aryl Nitriles

Ar

CN
Ar

+
N

aryl nitriles are prepared by heating a diazonium


salt with copper(I) cyanide
this is another type of Sandmeyer reaction
Dr. Wolf's CHM 201 & 202

21-140

Example

1. NaNO2, HCl,

NH2
CH3

H2O, 0C

CN
CH3

2. CuCN, heat
(64-70%)

Dr. Wolf's CHM 201 & 202

21-141

Transformations of Aryl Diazonium Salts


Ar
Ar

Cl

Ar

CN
+
N

Ar
Ar

Dr. Wolf's CHM 201 & 202

Ar

Ar

H
Ar

Br

OH
21-142

Transformations of Aryl Diazonium Salts


hypophosphorous acid (H3PO2) reduces diazonium
salts; ethanol does the same thing
this is called reductive deamination
+
N N
Ar
Ar

Dr. Wolf's CHM 201 & 202

21-143

Example

NaNO2, H2SO4,

NH2
CH3

H3PO2

CH3

(70-75%)

Dr. Wolf's CHM 201 & 202

21-144

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

Dr. Wolf's CHM 201 & 202

21-145

Example

NH2

Br2

NH2

Br

NaNO2, H2SO4,
Br
H2O, CH3CH2OH

H2O

Br

Br

Br

(100%)
Br
(74-77%)
Dr. Wolf's CHM 201 & 202

21-146

Azo Coupling

Dr. Wolf's CHM 201 & 202

21-147

Azo Coupling
Diazonium salts are weak electrophiles.
React with strongly activated aromatic compounds
by electrophilic aromatic substitution.

Ar

+
N

N + Ar'

Ar

Ar'

an azo compound
Ar' must bear a strongly electron-releasing group
such as OH, OR, or NR2.
Dr. Wolf's CHM 201 & 202

21-148

Example
OH

+
+ C6H5N

Cl

OH
N

Dr. Wolf's CHM 201 & 202

NC6H5
21-149

Spectroscopic Analysis of Amines

Dr. Wolf's CHM 201 & 202

21-150

Infrared Spectroscopy
the NH stretching band appears in the range
3000-3500 cm-1
primary amines give two peaks in this region, one
for a symmetrical stretching vibration, the other for
an antisymmetrical stretch
H
R

R
H

symmetric
Dr. Wolf's CHM 201 & 202

H
N
H
antisymmetric
21-151

Infrared Spectroscopy
primary amines give two NH stretching peaks,
secondary amines give one

RNH2

Dr. Wolf's CHM 201 & 202

R2NH

21-152

H NMR

compare chemical shifts in:

H3C

CH2NH2

H3C

3.9 ppm
N

H is more shielded than O

Dr. Wolf's CHM 201 & 202

CH2OH
4.7 ppm
C

H
21-153

C NMR

13

Carbons bonded to N are more shielded than


those bonded to O.

CH3NH2
26.9 ppm

Dr. Wolf's CHM 201 & 202

CH3OH
48.0 ppm
21-154

UV-VIS
An amino group on a benzene ring shifts max
to longer wavelength. Protonation of N causes
UV spectrum to resemble that of benzene.
+

NH2
NH3

max
204 nm
256 nm
Dr. Wolf's CHM 201 & 202

max
230 nm
280 nm

max
203 nm
254 nm
21-155

Mass Spectrometry

Compounds that contain only C, H, and O have


even molecular weights. If an odd number of N
atoms is present, the molecular weight is odd.
A molecular-ion peak with an odd m/z value
suggests that the sample being analyzed contains
N.

Dr. Wolf's CHM 201 & 202

21-156

Mass Spectrometry
Nitrogen stabilizes
carbocations, which
drives the fragmentation
pathways.

(CH3)2NCH2CH2CH2CH3
e
+

(CH3)2NCH2CH2CH2CH3

+
(CH3)2N
Dr. Wolf's CHM 201 & 202

CH2

+ CH2CH2CH3
21-157

Mass Spectrometry
Nitrogen stabilizes
carbocations, which
drives the fragmentation
pathways.

CH3NHCH2CH2CH(CH3)2
e
+

CH3NHCH2CH2CH(CH3)2

+
CH3NH
Dr. Wolf's CHM 201 & 202

CH2

+ CH2CH(CH3)2
21-158

End of Chapter 21

Dr. Wolf's CHM 201 & 202

21-159