Aromatic Amines
Dr Md Ashraful Alam
1
Aromatic Amines
• Aromatic Amines are organic nitrogen compounds, formed
by replacing one or more hydrogen atoms of ammonia (NH3)
with aryl groups.
• Like ammonia, the amine nitrogen atom has a nonbonded
electron pair, making it both a base and a nucleophile.
• Amines are stronger bases and better nucleophiles than
other neutral organic compounds.
H
H
C N
N
H
H
sp3
alkylamines
arylamines
2
• Amines are classified as:
– 1°, 2°, or , 3° amines: Amines in which there are 1, 2,
or 3 alkyl or aryl groups.
• 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.
N -H
Aniline
(a 1° aromatic amine)
N-Methylaniline
(a 2° aromatic amine)
CH3
CH2 - N- CH3
:
N H2
:
:
CH3
Benzyldimethylamine
(a 3° aliphatic amine)
3
Nomenclature
• Among the various functional groups, -NH2
is one of the lowest in order of precedence.
H2 N
OH
2-A min oeth anol
OH
NH2
(S )-2-Amin o-3-methyl1-bu tanol
Amine vs
alcohol
H2 N
COOH
4-A minoben zoic acid
Amine vs
acid
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.
H
CH3 NH2
NH2
N
Et 3 N
Methylamine tert -Butylamine Dicyclopen tylamine Triethylamin e
Nomenclature
• When four groups are bonded to nitrogen,
the compound is named as a salt of the
corresponding amine.
Nomenclature
• Aromatic amines are named as derivatives of aniline.
N H2
N H2
N H2
N H2
OCH3
Aniline
N O2
4-Nitroaniline
(p- Nitroaniline)
CH3
4-Methylaniline
(p-Toluidine)
3-Methoxyaniline
(m- Anisidine)
• There are many different nitrogen heterocycles, each with a different
name. The N atom is considered to be at position “1”.
N
N
H
H
Pyrrolidine Piperid ine
(h eterocyclic alip hatic amines)
N
N
H
Pyrrole
Pyridine
(h eterocyclic aromatic amin es)
7
Amines
Interesting and Useful Amines
• Many low molecular weight amines have foul odors.
• Trimethylamine [(CH3)3N], formed when enzymes break
down certain fish proteins, has the characteristic odor
of rotting fish.
• Putrescine (NH2CH2CH2CH2CH2NH2) and cadaverine
(NH2CH2CH2CH2CH2CH2NH2) are both poisonous
diamines with putrid odors. They too are present in
rotting fish, and are partly responsible for the odors of
semen, urine, and bad breath.
• Naturally occurring amines derived from plant sources
are called alkaloids.
Amines
Interesting and Useful Amines
• Histamine, a rather simple triamine that is
present in many tissues, is responsible for a
wide variety of physiological effects.
• Understanding the physiological properties of
histamine has helped chemists design drugs to
counteract some of its undesirable effects. Antihistamines bind
to the same active site as histamine in the cell, but they evoke a
different response. Examples are brompheniramine and
cimetidine.
Amines
Interesting and Useful Amines
Important Anilines
O
O
O
O Et
NEt2
NH2
NH2
procaine
benzocaine
CH3
H
N
NEt2
O
CH3
lidocaine
11
First useful antibiotic
Interesting and Useful Amines
• Histamine, a rather simple triamine that is
present in many tissues, is responsible for a wide
variety of physiological effects.
• Understanding the physiological properties of
histamine has helped pharmacists design drugs to
counteract some of its undesirable effects. Antihistamines bind to the
same active site as histamine in the cell, but they evoke a different
response. Examples are brompheniramine and cimetidine.
12
Interesting and Useful Amines
• A large number of physiologically active compounds are derived from
2-phenethylamine (C6H5CH2CH2NH2). These compounds include
adrenaline, noradrenaline, methamphetamine, and mescaline. Each
contains a benzene ring bonded to a two-carbon unit with a nitrogen
atom (shown in red).
13
Amines
Interesting and Useful Amines
• Another example is the neurotransmitter dopamine.
Amines
Interesting and Useful Amines
• Cocaine, amphetamines, and several other addicting
drugs increase the level of dopamine in the brain, which
results in a pleasurable “high.” With time, the brain
adapts to increased dopamine levels, so more drug is
required to produce the same sensation.
• Understanding the neurochemistry of these compounds
has led to the synthesis and availability of several
useful drugs. Examples are fentanyl and sumatripan.
Preparation of Amines
Reduction of N-Containing Functional Groups in nitro
compounds, nitriles and amides.
A nitro group (NO2) that has been introduced on a benzene
ring by nitration with strong acid can readily be reduced to
an amino group (NH2) under a variety of conditions.
NO2
HNO3
R
H2SO4
R
NH2
H2, Pd/C
-orFe, HCl
R
1° arylamine
NO2
SnCl2/acid
NH2
16
Preparation of Amines
Reductive Amination: The most effective reducing agent for
this reaction is sodium cyanoborohydride (NaBH3CN).
17
Reactions of Amines—General Features
• The chemistry of amines is dominated by the nonbonded
lone pair of electrons on nitrogen.
• Amines react with electrophiles to form quaternary
ammonium salts—compounds with four bonds to nitrogen.
18
Basicity of Amines. The basicity is expressed as the pKa’s of
the conjugate acid.
The conjugate base of a weak acid is a strong base:
Higher pKa = weaker acid = stronger conjugate base
The conjugate base of a strong acid is a weak base
Lower pKa = stronger acid = weaker conjugate base
pKa values of ammonium ions
The ammonium ions of aryl amines and heterocyclic aromatic
amines are considerably more acidic than alkyl amines (pKa <
5). The nitrogen lone pair is less basic if it is in an sp2
hybridized orbital (versus an sp3)
+
NH4+
(H3CH2C)NH3
NH3
pKa= 9.3
+
10.8
(H3CH2C)2NH2+
11.1
(H3CH2C)3NH+
10.8
Alkyl ammonium
ions, R3NH+ X-
pKa= 4.6
+
N H
+ H
N
H
+
5.2
0.4
19
Amines as Bases
• The relative basicity of different compounds (such as amines) can
be compared using the pKa values of their conjugate acids.
• To compare the basicity of two compounds, keep in mind that (1)
any factor that increases the electron density on the N atom
increases the amines basicity; (2) any factor that decreases the
electron density on N decreases an amines basicity.
The ammonium ions of aryl amines and heterocyclic
aromatic amines are considerably more acidic than alkyl
amines (pKa < 5)
20
Amines as Bases
• To compare an alkylamine and an arylamine, we must look at the
availability of the nonbonded electron pair on N.
• With CH3CH2NH2 for example, the electron pair is localized on the
N atom. With an arylamine, the electron pair is delocalized on the
benzene ring. This decreases the electron density on N, and makes
an amine like C6H5NH2 less basic than CH3CH2NH2.
21
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
N H
H .
.
H + H
N
H
un hybridized 2p orb ital of N
..
.
.
H .
H
H+ H
N
.
N
H
H + H
N
H
H
nitrogen is sp 2 h yb rid ized
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.
The effect of substitutents is dependent upon the
nature and position of the substitutent.
• Electron-releasing groups (-CH3, -OH, -OCH3) increase
the basicity of aromatic amines.
• Electron-withdrawing groups (-Cl, -NO2 , -C=O) decrease
the basicity of aromatic amines by a combination of
resonance and inductive effects.
Y
+
NH3
+ H2O
Y= -NH2
-OCH3
-CH3
-H
-Cl
-CF3
-CN
-NO2
Y
pKa= 6.2
pKa= 5.3
pKa= 5.1
pKa= 4.6
pKa= 4.0
pKa= 3.5
pKa= 1.7
pKa= 1.0
NH2
+
+ H3O
less acidic
(more basic)
more acidic
(less basic)
24
Electrophilic Aromatic Substitution in Arylamines
The amino group is strongly activating, ortho/para director;
however, it is largely incompatible with Friedel-Crafts reactions.
EAS of phenyl acetamides (amides of aniline). The acetamide
group is still activating and an ortho/para director.
O
NH2
(H3CCO)2O,
pyridine
CH3
HN
O
NH2
CH3
HN
Br2
CH3
Br
CH3
Br
NaOH, H2O
CH3
CH3
The acetamides is acts as a protecting group for the arylamine
Anilines are so activated that multiple substitution reactions can
be a problem. The reactivity of the acetamide is attenuated so
that mono substitution is achieved.
The acetamide group is compatiable with the Friedel-Crafts
25
reactions
Amines as Nucleophiles
• The conversion of amines to amides is useful in the synthesis of
substituted anilines.
• Aniline itself does not undergo Friedel-Crafts reactions because
the lone pair on N reacts with the Lewis acid (AlCl3) to form a
deactivated complex that does not undergo further reaction.
• The N atom of an amide, however, is much less basic than the N
atom of an amine, so it does not undergo a similar Lewis acidbase reaction with AlCl3. Thus, a three-step reaction sequence
involving an intermediate amide can be used to form the products
26
of the Friedel-Crafts reaction.
Amines as Nucleophiles
27
Reaction of Amines with Nitrous Acid
Nitrous acid reacts with 1° alkylamines and arylamines to form
diazonium salts. This reaction is called diazotization.
Substitution Reactions of Aryl Diazonium Salts
• Aryl diazonium salts react with a variety of reagents to
form products in which Z (an atom or group of atoms)
replaces N2, a very good leaving group.
• The mechanism of these reactions varies with the identity of
Z.
28
Reaction of Amines with Nitrous Acid
Amines
Reaction of Amines with Nitrous Acid
• Alkyl diazonium salts are generally not useful
compounds.
• They readily decompose below room temperature and
form carbocations with loss of N2, a very good leaving
group.
• These carbocations usually form a complex mixture of
substitution, elimination and rearrangement products.
Synthetic Transformations of Aryl Diazonium Salts.
N
X
N
N
N
Nu
+
+ Nu:
Cu2O,
H2O
NaI
OH
HCl,
CuCl
HBF4
I
F
HBr,
CuBr
Cl
Cu(CN)
Br
N N
H3PO2
CN
H
Advantages of the aryl diazonium salt intermediate:
1) Introduces aryl substituents that are not otherwise
accessible, such as -OH, -F, -I, and -CN.
2) Allows preparation of substituted arenes with substitution
patterns that can not be prepared by other means.
31
Substitution Reactions of Aryl Diazonium Salts
A diazonium salt reacts with water to form a phenol.
A diazonium salt reacts with copper(I) chloride or copper(I) bromide to form
an aryl chloride or aryl bromide. This is called the Sandmeyer reaction.
32
Substitution Reactions of Aryl Diazonium Salts
A diazonium salt reacts with fluoroboric acid to form an aryl fluoride.
This is a useful reaction because aryl fluorides cannot be produced by
direct fluorination with F2 and a Lewis acid catalyst.
A diazonium salt reacts with sodium or potassium iodide to form an
aryl iodide. This is a useful reaction because aryl iodides cannot be
produced by direct iodination with I2 and a Lewis acid catalyst.
33
Substitution Reactions of Aryl Diazonium Salts
A diazonium salt reacts with copper(I) cyanide to form benzonitrile.
Since the cyano group can be converted into a variety of other
functional groups, this reaction provides easy access to a wide variety
of benzene derivatives.
A diazonium salt reacts with hypophosphorus acid to form benzene.
This reaction is useful in synthesizing compounds that have substitution
34
patterns that are not available by other means.
Substitution Reactions of Aryl Diazonium Salts
• Br is an o,p director, bromination with Br2 and FeBr3 will not
add Br substituents meta to each other on the ring.
• It is possible, however, to add three Br atoms meta to each
other when aniline is the starting material. Then, the NH2 group
can be removed by diazotization and reaction with H3PO2.
35
Substitution Reactions of Aryl Diazonium Salts
The synthesis of 1,3,5-tribromobenzene from benzene
36
Substitution Reactions of Aryl Diazonium Salts
• Diazonium salts provide easy access to many different
benzene derivatives. Keep in mind the following four-step
sequence, because it will be used to synthesize many
substituted benzenes.
37
Coupling Reactions of Aryl Diazonium Salts
• When a diazonium salt is treated with an aromatic
compound that contains a strong electron-donor group, the
two rings join together to form an azo compound, a
compound with a nitrogen—nitrogen double bond.
• Azo compounds are highly conjugated, rendering them
colored. Many of these compounds are synthetic dyes.
Butter yellow was once used to color margarine.
38
Amines
Natural and Synthetic Dyes
• Three natural dyes known for centuries are indigo,
tyrian purple, and alizarin.
Amines
Natural and Synthetic Dyes
• In 1856 William Henry Perkin synthesized mauveine, a
mixture of two compounds that differ only in the
presence of one methyl group on one of the aromatic
rings.
Amines
Natural and Synthetic Dyes
• Many common synthetic dyes such as alizarine yellow
R, para red, and Congo red, are azo compounds.
Amines
Natural and Synthetic Dyes
• To be classified as a dye, a compound must be colored
and it must bind fabric.
• Compounds that bind to fabric by some type of
attractive force are called direct dyes.
• The attractive forces may be electrostatic interactions,
van der Waals forces, hydrogen bonding, and
sometimes even covalent bonding—The type of
interaction depends on the structure of the dye and the
fiber.
• A compound that may be good for dying wool or silk,
both polyamides, may be poor for dying cotton, a
carbohydrate.
Amines
Natural and Synthetic Dyes
• Wool and silk contain charged functional groups, such
as NH3+ and COO¯. Thus, they bind to ionic dyes by
electrostatic interactions.
• Positively charged NH3+ groups bonded to the protein
backbone are electrostatically attracted to anionic
groups in a dye like methyl orange.
Amines
Natural and Synthetic Dyes
• Cotton, on the other hand, binds dyes by hydrogen
bonding interactions with its many OH groups. Thus,
Congo red is bound to the cellulose backbone by
hydrogen bonds.
Amines
Sulfa Drugs
• In 1935, Gerhard Domagk first used a synthetic dye,
prontosil, to kill bacteria.
• Prontosil and other sulfur containing antibiotics are
collectively known as sulfa drugs.
• Prontosil is not the active ingredient itself—In cells, it is
metabolized to sulfanilamide, the active drug.
Amines
Sulfa Drugs
• To understand how sulfanilamide functions as an
antibacterial agent, we must examine folic acid, which
microorganisms synthesize from p-aminobenzoic acid.
• Sulfanilamide and p-aminobenzoic acid are similar in size
and shape and have related functional groups.
Amines
Sulfa Drugs
• When sulfanilamide is administered, bacteria attempt to use
it in place of p-aminobenzoic acid to synthesize folic acid.
Derailing folic acid synthesis means that the bacteria cannot
grow and reproduce. Sulfanilamide only affects bacterial
cells, because humans do not synthesize folic acid, and
must obtain it from their diets.
Example of biologically active
amines
H2NCH2CH2CH2CH2NH2
putrescine
H2NCH2CH2CH2CH2NCH2CH2CH2CH2NH2
spermidine
H
H2NCH2CH2CH2CH2CH2NH2
H2N(CH2)N(CH2)4N(CH2)3NH2
H
H spermine
H OH
HO
H OH
NHCH3
HO
NH2
HO
HO
epinephrine
(adrenaline)
cadaverine
HO
NH2
HO
dopamine
norepinephrine
(noradrenaline)
More biologically active
amines…
H CH3
H CH3
NH2
NHCH3
CH3O
NH2
CH3O
amphetamine
(benzadrine)
OCH3
methamphetamine
(speed)
mescaline
CH2CH2NH2
CO2H
N
N
N
nicotinic acid
(niacin)
CH2CH2NH2
HO
serotonin
H
N
histamine
H
More biologically active
amines…
H
O
O
H
N
CH3CH2O
Cl
CH3
N
N
N
N
N
CH2CH2CH3
O
O S N
O
diazepam (Valium)
O
H2N
C OCH2CH3
benzocaine
(a topical anesthetic)
N
CH3
Sildenafil (Viagra)
More biologically active
amines…
RO
O
H3C
O
CH3
N
C OCH
3
H
N
O
H
CH3
R'O
O
N
N
N
O
NCH3
H3C
C
cocaine
caffeine
O
codeine (R = CH3, R' = H)
morphine (R and R' = H)
heroin (R and R' = COCH3)
CH3
H
N
N
CH3
nicotine
CH3CH2O
C
NCH3
CH3CH2
C
C6H5 NCH3
O
O
mepiridine
(Demerol)
CH3
Methadone
More biologically active
amines…
H
H
O
(CH3CH2)2N
C
H
N
CH3
N
N
HO
H
H
N
N
quinine
N
O
H
strychnine
lysergic acid diethylamide (LSD)
H
N
CH2CH2CH3
H
coniin (the poison from
hemlock used to kill Socrates)
O