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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)
ethylamine or ethanamine
CH3CH2NH2
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
F
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
CH3
N
CH3
N,N-dimethylcycloheptylamine
Dr. Wolf's CHM 201 & 202
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
+
–
N CH2CH3 CF3CO2
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 I
–
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
C
NH
C
2
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 C—N bond makes with bisector of
H—N—H angle is a measure of geometry at N.
sp3
~125°
sp2
180°
Note: this is not the same as the H—N—H
bond angle
Dr. Wolf's CHM 201 & 202
21-17
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°
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:
-42°C
17°C
78°C
Dr. Wolf's CHM 201 & 202
21-23
Physical Properties
CH3CH2CH2NH2 CH3CH2NHCH3
boiling
point:
50°C
34°C
(CH3)3N
3°C
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 pK = 4.6
a
acid
H +
NH2 +
Dr. Wolf's CHM 201 & 202
H2N
H
••
Weaker
base
••
Stronger
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.
••
NH2 +
Stronger
base
+
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
pKa of conjugate acid:
4.6
Dr. Wolf's CHM 201 & 202
(C6H5)2NH
(C6H5)3N
0.8
~-5
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
– ••
•• O ••
••
O ••
+
N
•• O ••
– ••
••
NH2
+
N
+
NH2
•• O ••
– ••
Lone pair on amine nitrogen is conjugated with
p-nitro group—more 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
N
N
H
piperidine
pyridine
pKa of conjugate acid:
11.2
pKa of conjugate acid:
5.2
(an alkylamine)
(resembles an
arylamine in
basicity)
Dr. Wolf's CHM 201 & 202
••
21-40
Heterocyclic Amines
•• N
•• N
is more basic than
H
N
••
imidazole
pyridine
pKa of conjugate acid:
7.0
pKa of conjugate acid:
5.2
Dr. Wolf's CHM 201 & 202
21-41
Imidazole
Which nitrogen is protonated in imidazole?
•• N
•• N
H
H+
+
H N
Dr. Wolf's CHM 201 & 202
H+
•N
•
H
•• N
+ H
N
H
21-42
Imidazole
Protonation in the direction shown gives a
stabilized ion.
•• N
•• N
H
H+
+
H N
Dr. Wolf's CHM 201 & 202
•N
•
H
H
N ••
+
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.
H3C
CH2CH2CH2CH2CH2CH2CH2CH3
+
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
CH2CH3
+
N CH2CH3 Cl–
CH2CH3
CN–
+
(aqueous)
(aqueous)
CH2CH3
+
N CH2CH3 CN–
CH2CH3
(aqueous)
Dr. Wolf's CHM 201 & 202
+
Cl–
(aqueous)
21-49
Mechanism
CH2CH3
+
N CH2CH3 CN–
CH2CH3
(in butyl bromide)
CH2CH3
+
N CH2CH3 CN–
CH2CH3
(aqueous)
Dr. Wolf's CHM 201 & 202
21-50
Mechanism
CH2CH3
+
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 C—N 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 C—N 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 a-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
+
R—X
R—NH2 +
NH4X
+
H3N
•• –
•• X ••
••
via:
H3N •• + R
then:
H3N •• + H
Dr. Wolf's CHM 201 & 202
••
X ••
••
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
Dr. Wolf's CHM 201 & 202
X
–
RX
R3 N
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 C—N 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 C—N bond
the nitrogen-containing nucleophile
is N-potassiophthalimide
O
–
•• N •
•
K
+
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
O
O
•• NH
O
Dr. Wolf's CHM 201 & 202
KOH
–
•• N •
•
K
+
O
21-62
N-Potassiophthalimide as a nucleophile
O
O
–
•• N • + R
•
••
X ••
SN2
•• N
••
O
O
+
Dr. Wolf's CHM 201 & 202
R
•• –
•• X ••
••
21-63
Cleavage of Alkylated Phthalimide
O
•• N
R + H2O
O
imide hydrolysis is
nucleophilic acyl
substitution
acid or base
CO2H
+
H2N
R
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
O
•• N
R
H2NNH2
NH
NH
O
O
+
Dr. Wolf's CHM 201 & 202
H2N
R
21-65
Example
O
–
•N •
• •
K
+
+
C6H5CH2Cl
DMF
O
O
•• N
CH2C6H5
(74%)
O
Dr. Wolf's CHM 201 & 202
21-66
Example
O
NH
+
C6H5CH2NH2 (97%)
NH
H2NNH2
O
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.
NaCN
CH3CH2CH2CH2Br
nitriles may also be
reduced by lithium
aluminum hydride
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.
NaCN
CH3CH2CH2CH2Br
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
Cl
(88-95%)
1. Fe, HCl
2. NaOH
NH2
(95%)
Dr. Wolf's CHM 201 & 202
NO2
Cl
21-73
Synthesis of Amines via Amides
O
COH
O
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'
R
O + NH3
C
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
R
O + NH3
C
R'
Dr. Wolf's CHM 201 & 202
C
H
NH +
H2O
R'
R
R'
C
H2, Ni
NH2
21-77
Example: Ammonia gives a primary amine.
O + NH3
H2, Ni
H
ethanol
NH2
(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
via:
Dr. Wolf's CHM 201 & 202
CH3(CH2)5CH
(65%)
N
21-79
Example: Secondary amines give tertiary amines
O
CH3CH2CH2CH
+
N
H
H2, Ni, ethanol
N
Dr. Wolf's CHM 201 & 202
CH2CH2CH2CH3
(93%)
21-80
Example: Secondary amines give tertiary amines
possible intermediates include:
HO
N
+
N
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:
N ••
H
X
as a nucleophile:
N ••
C
O
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
+
•• –
N R + •• X ••
••
X ••
••
••
H
H
N
••
Dr. Wolf's CHM 201 & 202
R
+
H
+
21-86
Example: excess amine
NH2
+
ClCH2
(4 mol)
(1 mol)
NaHCO3
90°C
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
–
H2O, CH3OH
+
–
CH2N (CH3)3 HO
Dr. Wolf's CHM 201 & 202
21-91
The Hofmann Elimination
on being heated, quaternary ammonium
hydroxides undergo elimination
CH2 +
N(CH3)3
+
H2O
(69%)
160°C
+
–
CH2N (CH3)3 HO
Dr. Wolf's CHM 201 & 202
21-92
Mechanism
– ••
•• O
••
••
O
••
H
H
H
H
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
CHCH2CH3 (95%)
heat
+ N(CH3)3
HO
–
Dr. Wolf's CHM 201 & 202
+
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
H
CH3CH2
H
H
H
H
CH3CH2
+ N(CH3)3
H
C
C
H
major product
largest group is between two H atoms
Dr. Wolf's CHM 201 & 202
21-96
Regioselectivity
H
H
CH3
CH3
H
+ N(CH3)3
CH3
H
H
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
NH2
NO2
KOH
ethanol,
heat
CH(CH3)2
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
O
O
NHCCH3
NHCCH3
CH3
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.
O
O
NHCCH3
CH3
NHCCH3
O
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
– ••
•• O
••
••
O ••
N
••
H
+
••
O
H
••
O ••
N
H
H
••
••
+
H
• O ••
•
+
H
Dr. Wolf's CHM 201 & 202
••
N
+
+
•• O
••
O ••
••
N
••
O ••
H
21-107
Nitrosyl Cation and Nitrosation
••
N
+
Dr. Wolf's CHM 201 & 202
••
O ••
21-108
Nitrosyl Cation and Nitrosation
+
N
N ••
+
Dr. Wolf's CHM 201 & 202
••
••
O ••
N
••
N
+
••
O ••
21-109
Nitrosation of Secondary Alkylamines
+
N
••
••
O ••
N
•• N
O ••
N
+
H
H
N ••
••
••
+
H
Dr. Wolf's CHM 201 & 202
••
N
+
••
O ••
+
nitrosation of
secondary amines
gives an N-nitroso
amine
21-110
Example
••
(CH3)2NH
Dr. Wolf's CHM 201 & 202
NaNO2, HCl
H2O
••
(CH3)2N
••
N
••
O ••
(88-90%)
21-111
Some N-Nitroso Amines
(CH3)2N
N
O
N-nitrosodimethylamine
(leather tanning)
N
N
N
N
O
N-nitrosopyrrolidine
(nitrite-cured bacon)
Dr. Wolf's CHM 201 & 202
N
O
N-nitrosonornicotine
(tobacco smoke)
21-112
Nitrosation of Primary Alkylamines
R
H
R
+
N
••
N
••
O ••
•• N
H
H
H
N ••
+
H
Dr. Wolf's CHM 201 & 202
••
N
+
••
O ••
O ••
N
+
H
R
••
••
+
analogous to
nitrosation of
secondary amines
to this point
21-113
Nitrosation of Primary Alkylamines
R
•• N
••
N
H
•• +
H
•• N
H
N
+
Dr. Wolf's CHM 201 & 202
O ••
H
O ••
N
H
R
••
••
••
•• N
O
H
••
+
R
H
+
this species reacts further
R
H
•• N
••
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
N ••
+
•• O ••
H
R
•• N
H
••
N
O ••
+
H
Dr. Wolf's CHM 201 & 202
21-115
Alkyl Diazonium Ions
+ + •N
R
•
N ••
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
NH2
OH
+
N
HONO
H2O
N
– N2
+
(80%)
+
(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
R
R
+
N
N ••
R
Dr. Wolf's CHM 201 & 202
••
N
••
O ••
R
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, 8°C
N(CH2CH3)2
2. HO–
N
O
(95%)
Dr. Wolf's CHM 201 & 202
21-120
Nitrosation of N-Alkylarylamines
similar to secondary alkylamines;
gives N-nitroso amines
NaNO2, HCl,
H2O, 10°C
NHCH3
N
O
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 (0-10°C)
+
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, 0-5°C
(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
F
Ar
I
N
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, 0-5°C
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
F
Ar
I
N
H
Ar
Br
OH
21-129
Preparation of Aryl Iodides
reaction of an aryl diazonium salt with
potassium iodide
Ar
+
N
N
KI
Ar
Dr. Wolf's CHM 201 & 202
I
21-130
Example
NH2
Br
1. NaNO2, HCl
H2O, 0-5°C
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
F
Ar
I
N
H
Ar
Br
OH
21-132
Preparation of Aryl Fluorides
Ar
Ar
+
N
F
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, 0-5°C
CCH2CH3
O
2. HBF4
3. heat
F
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
F
Ar
I
N
H
Ar
Br
OH
21-135
Preparation of Aryl Chlorides and Bromides
Ar
Cl
Ar
Ar
+
N
Br
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
Dr. Wolf's CHM 201 & 202
21-136
Example
NH2
1. NaNO2, HCl,
H2O, 0-5°C
NO2
2. CuCl, heat
Cl
NO2
(68-71%)
Dr. Wolf's CHM 201 & 202
21-137
Example
NH2
Cl
1. NaNO2, HBr,
H2O, 0-10°C
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
F
Ar
I
N
H
Ar
Br
OH
21-139
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
Dr. Wolf's CHM 201 & 202
21-140
Example
NH2
CH3
1. NaNO2, HCl,
H2O, 0°C
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
F
Ar
I
N
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
H
Dr. Wolf's CHM 201 & 202
21-143
Example
NH2
CH3
NaNO2, H2SO4,
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
NH2
Br2
NaNO2, H2SO4,
Br H O, CH CH OH
2
3
2
Br
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.
+
N N + Ar' H
N
Ar
Ar
N
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
N
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 N—H 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
N
R
H
symmetric
Dr. Wolf's CHM 201 & 202
H
N
H
antisymmetric
21-151
Infrared Spectroscopy
primary amines give two N—H stretching peaks,
secondary amines give one
RNH2
Dr. Wolf's CHM 201 & 202
R2NH
21-152
1H
NMR
compare chemical shifts in:
H3C
CH2NH2 H3C
 3.9 ppm
N
C
H is more shielded than O
Dr. Wolf's CHM 201 & 202
CH2OH
 4.7 ppm
C
H
21-153
13C
NMR
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.
+
NH3
NH2
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