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Organic Chemistry
4th Edition
Paula Yurkanis Bruice
Chapter 21
More About Amines.
Heterocyclic
Compounds
Irene Lee
Case Western Reserve University
Cleveland, OH
©2004, Prentice Hall
Amines
• An amine is a base as well as a nucleophile
• Some amines are heterocyclic compounds
(or heterocycles)
• Most drugs, vitamins, and many other natural products
are heterocycles
• A natural product is a compound synthesized by a plant
or an animal
Alkaloids are natural products that contain one or
more nitrogen heteroatoms
More About Nomenclature of Heterocycles
Cyclic amines
CH3
H
N
NH
N
H
azacylclopropane
aziridine
N
H
azacyclobutane
azetidine
CH3
3-methylazacyclopentane
3-methylpyrrolidine
N
CH2CH3
2-methylazacyclohexane
2-methylpiperidine
N-ethylazacyclopentane
N-ethylpyrrolidine
Heterocycles with oxygen and sulfur heteroatoms
O
S
oxacyclopropane
oxirane
ethylene oxide
thiacyclopropane
thiirane
O
oxacyclobutane
oxetane
O
O
oxacyclopentane
tetrahydrofuran
O
O
tetrahydropyran
1,4-dioxane
The lone-pair electrons on nitrogen allows an amine to
turn “inside out” rapidly at room temperature
Amines are the most common organic bases
Saturated heterocycles containing five or more atoms
have physical and chemical properties typical of their
acyclic analogs
Reactions of Amines
nucleophilic substitution reactions
CH3CH2Br
CH3NH2
+
CH3CH2NHCH3
CH3CH2NH2CH3
+ HBr
Br
nucleophilic acyl substitution reactions
O
O
C
CH3CH2
+
Cl
C
2 CH3NH2
CH3CH2
+
NHCH3
CH3NH3Cl
nucleophilic addition–elimination reactions
O
+
N
HN
+ H2O
conjugate addition reactions
CH3
CH3C
CH3
O
CHCH
+
CH3NH
CH3
CH3C
NCH3
CH3
O
CH2CH
Relative Reactivity of Amine
most reactive
least reactive
RCH2F > RCH2OH ~ RCH2OCH3 > RCH2NH2
HF
H2O
RCH2OH
NH3
pKa = 3.2
pKa = 15.7
pKa = 15.5
pKa = 36
The leaving group of a protonated amine cannot
dissociate to form a carbocation or be replaced by a
halide ion
Reactions of Quaternary Ammonium Hydroxides
A Hofmann elimination is an E2 reaction
The leaving group of a quaternary ammonium ion has
about the same leaving tendency as a protonated amino
group
The hydrogen is removed from the b-carbon bonded to
the most hydrogens
A strong base such as hydroxide ion must be used in the
elimination reaction
Quaternary ammonium salts are used as phase transfer
catalysts in facilitating the reactions between certain
ionic and organic reactants
Consider the reaction between sodium cyanide and an
alkyl halide …
Oxidation of Amines
oxd
oxd
R
NH2
R
NH
OH
R
N
O
O
O-
R
R
R
NH
+ H2O2
R
H + OH-
N+
R
R
N
OH
R
R
R
+ H2O2
R
+
H2O
N
OH
R
N+
R
a nitroso
compound
a hydroxylamine
R
oxd
N+
OH
R + OH-
R
N
O_
+
H2O
R
Amine Oxides Undergo a
Cope Elimination Reaction
The Gabriel Synthesis of Primary Amines
Other Methods for Synthesizing Amines
1. N3
CH3CH2CH2CH2Br
-
2. H2, Pd/C
1. NaCN, HCl
2. H2, Pd/C
CH3CH2CH2CH2CH2NH2
CH3CH2CH2CH2NH2
O
1. LiALH4
R
NH2
2. H2O
RCH2NH2
O
1. LiALH4
R
NHCH3
2. H2O
RCH2NHCH3
1. LiALH4
RCH2NCH3
O
R
NCH3
CH3
2. H2O
CH3
Reduction of Nitro Compounds
Pd/C
CH3CH2NO2 +
NO2
H2
+
CH3CH2NH2
H2
Pd/C
NH2
Reductive Amination
Secondary and tertiary amines can be prepared from
imines and enamines by reducing the imines or enamines
Aromatic Five-Membered Heterocycles
Pyrrole is an extremely weak base
The dipole moment in pyrrolidine (left) is attributed to
the electron-withdrawing property of the nitrogen atom
Pyrrole, furan, and thiophene undergo electrophilic
substitution preferentially at C-2
The relative reactivities of the five-membered-ring
heterocycles in Friedel–Crafts reaction
The resonance hybrid of pyrrole indicates that there is a
partial positive charge on the nitrogen
Pyrrole is unstable in strongly acid solution because the
protonated pyrrole polymerizes
Pyrrole’s acidity is increased due to its conjugated base
being stabilized by resonance
N
H
O
benzofuran
indole
S
benzothiophene
Aromatic Six-Membered-Ring Heterocycles
The pyridinium ion is a stronger acid than a typical
ammonium ion
Pyridine Is a Tertiary Amine
Pyridine undergoes electrophilic aromatic substitution at
C-3
Pyridine undergoes nucleophilic aromatic substitution at
C-2 and C-4
Bromination and Oxidation of
Substituted Pyridine
Diazotization of Aminopyridine
The a-hydrogens of alkyl substituents can be removed by
base to generate nucleophiles
Quinoline and isoquinoline are known as benzopyridines
Some Biologically Important Heterocycles
Imidazole
Porphyrin