Heterocyclic

Compounds
 Amines
• An amine is a base as well as a nucleophile

• Some amines are heterocyclic compounds

(or heterocycles)
A heteroatom is an atom other than carbon. The
name comes from the Greek word heteros, which
means “different.” A variety of atoms, such as N, O, S,
Se, P, Si, B, and As, can be incorporated into ring
structures.
• A natural product is a compound synthesized by a
plant or an animal
• Most drugs, vitamins, and many other natural products
are heterocycles
Alkaloids are natural products that contain one or
more nitrogen heteroatoms
 More About Nomenclature of Heterocycles
Cyclic amine without any double bonds—can be
named as a cycloalkane, using the prefix “aza” to
denote the nitrogen atom.
CH3

H N
N NH H
3-methylazacyclopentane
3-methylpyrrolidine
azacylclopropane azacyclobutane
aziridine azetidine
N

N CH3 CH2CH3
H
2-methylazacyclohexane N-ethylazacyclopentane
2-methylpiperidine N-ethylpyrrolidine
Heterocycles with oxygen and sulfur heteroatoms
The prefix for oxygen is “oxa” and that for sulfur is
“thia.”
O S O

oxacyclopropane thiacyclopropane oxacyclobutane

oxirane thiirane oxetane
ethylene oxide

O O O
oxacyclopentane tetrahydropyran 1,4-dioxane
tetrahydrofuran
Amines are the most common organic bases

Saturated heterocycles containing five or more atoms

have physical and chemical properties typical of their
acyclic analogs
 Aromatic Five-Membered Heterocycles
• Pyrrole, furan, and thiophene has three pairs of delocalized electrons:
Two of the pairs are shown as bonds, and one pair is shown as a lone
pair on the heteroatom.
• Furan and thiophene have a second lone pair which these electrons are
in an orbital perpendicular to the p orbitals.
• Pyrrole, furan, and thiophene are aromatic because they are cyclic and
planar, every carbon in the ring has a p orbital, and the cloud contains
three pairs of electrons
Pyrrole is an extremely weak base

Conjugate acid of pyrrole is a very strong acid

(pKa = -3.82) that is, it has a strong tendency
to lose a proton.
The dipole moment in pyrrolidine (left) is attributed to
the electron-withdrawing property of the nitrogen atom
The more stable and more nearly equivalent the
resonance contributors, the greater is the resonance
energy.

Thiophene, with the least electronegative heteroatom,

has the greatest resonance energy of these five-
membered heterocycles; and furan, with the most
electronegative heteroatom, has the smallest
resonance energy
Pyrrole, furan, and thiophene undergo electrophilic
substitution preferentially at C-2
Substitution occurs preferentially at C-2 because the
intermediate obtained by attaching a substituent at
this position is more stable than the intermediate
obtained by attaching a substituent at C-3
Pyrrole, furan, and thiophene are all more reactive than
benzene toward electrophilic substitution because they
are better able to stabilize the positive charge on the
carbocation intermediate, since the lone pair on the
hetereoatom can donate electrons into the ring by
resonance.
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 O S
H
indole benzofuran 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 electron-withdrawing nitrogen causes
the a-hydrogens of alkyl groups attached to
the 2- and 4-positions of the pyridine ring to
have about the same acidity as the a-
hydrogens of ketones.
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
Both protonated imidazole and the imidazole anion
have two equivalent resonance contributors. This
means that the two nitrogens become equivalent when
imidazole is either protonated or deprotonated.
Porphyrin