1 The Structure of Heterocyclic Compounds

Most chemical compounds consist of molecules. The classification of such chemical compounds is
based on the structure of these molecules, which is defined by the type and number of atoms as well as
by the covalent bonding within them. There are two main types of structure:
— The atoms form a chain - aliphatic (acyclic) compounds
— The atoms form a ring - cyclic compounds
Cyclic compounds in which the ring is made up of atoms of one element only are called isocyclic com-
pounds. If the ring consists of C-atoms only, then we speak of a carbocyclic compound, e.g.:

NMe?
O
(4 - dimethylaminophenyl) pentazole cyclopenta -1,3 - diene
isocyclic isocyclic und carbocyclic

Cyclic compounds with at least two different atoms in the ring (as ring atoms or members of the ring)
are known as heterocyclic compounds. The ring itself is called a heterocycle. If the ring contains no
C-atom, then we speak of an inorganic heterocycle, e.g.:

MeO

2,4 - bis (4 - methoxyphenyl) -

1,3 - dithiadiphosphetan -2,4 - disulfide borazine
(Lawesson - Reagent)

If at least one ring atom is a C-atom, then the molecule is an organic heterocyclic compound. In this
case, all the ring atoms which are not carbon are called heteroatoms, e.g.:

The Chemistry ofHeterocycles, Second Edition. By Theophil Eicher and Siegfried Hauptmann
Copyright © 2003 Wiiey-VCH Veriag GmbH & Co. KGaA
ISBN: 3-527-30720-6
 The Structure of Heterocyclic Compounds

oxazole 4 - H -1,4 - thiazine

heteroatoms O and N heteroatoms S and N

In principle, all elements except the alkali metals can act as ring atoms.
Along with the type of ring atoms, their total number is important since this determines the ring size.
The smallest possible ring is three-membered. The most important rings are the five- and six-
membered heterocycles. There is no upper limit; there exist seven-, eight-, nine- and larger-membered
heterocycles.
Although inorganic heterocycles have been synthesized, this book limits itself to organic com-
pounds. In these, the N-atom is the most common heteroatom. Next in importance are O- and S-atoms.
Heterocycles with Se-, Te-, P-, As-, Sb-, Bi-, Si-, Ge-, Sn-, Pb- or B-atoms are less common.
To determine the stability and reactivity of heterocyclic compounds, it is useful to compare them
with their carbocyclic analogues. In principle, it is possible to derive every heterocycle from a carbo-
cyclic compound by replacing appropriate CH2 or CH groups by heteroatoms. If one limits oneself to
monocyclic systems, one can distinguish four types of heterocycles as follows:

• Saturated heterocycles (heterocycloalkanes), e.g.:

C
cyclohexane X = O oxane X = O 1,4-dioxane
X = S thiane X = S 1,4-dithiane
X = NH piperidine X = NH piperazine

In this category, there are no multiple bonds between the ring atoms. The compounds react largely like
their aliphatic analogues, e.g. oxane (tetrahydropyran) and dioxane behave like dialkyl ethers, thiane
and 1,4-dithiane like dialkyl sulfides, and piperidine and piperazine like secondary aliphatic amines.

Partially unsaturatedsystems (heterocycloalkenes)', e.g.:

O
cyclohexene X = O 3,4-dihydro-2H-pyran
X =S
X = NH
 The Structure of Heterocyclic Compounds

0
X = O 3,4-dJhydro-1,4-dioxin X = O®
X=S X=S®
X = NH X = NH 2,3,4,5-tetrahydropyridine

If the multiple bonds are between two C-atoms of the ring, as, for instance, in 3,4-dihydro-2//-pyran,
the compounds react essentially like alkenes or alkynes. The heteroatom can also be involved in a dou-
ble bond. In the case of X = O+, the compounds behave like oxenium salts, in the case of X = S+, like
sulfenium salts, and in the case of X = N, like imines (azomethines).

• Systems with the greatest possible number of noncumulated double bonds (heteroannulenes), e.g.:

[6]annulene X = O® pyryliumsalts X=N pyrimidine

benzene X = S® thiiniumsalts
X = N py rid ine,
pyridine-like N - atom

o
X = 0 furan
X = S thiophene
X = NH pyrrole,
pyrrole-like N - atom

[8]annulene X = cP X = N 1,3 - diazocine

cyclooctatetraene X =S
X = N azocine .

X = 0 oxepine
X =S thiepine
X = NH azepine
 The Structure of Heterocyclic Compounds

From the annulenes, one can formally derive two types of heterocycles:
— systems of the same ring size, if CH is replaced by X
— systems of the next lower ring size, if HC=CH is replaced by X.
In both cases, the resulting heterocycles are iso-^-electronic with the corresponding annulenes, i.e. the
number of ^-electrons in the ring is the same. This is because in the pyrylium and thiinium salts, as
well as in pyridine, pyrimidine, azocine and 1,3-diazocine, each heteroatom donates one electron pair
to the conjugated system and its nonbonding electron pair does not contribute. However, with furan,
thiophene, pyrrole, oxepin, thiepin and azepine, one electron pair of the heteroatom is incorporated into
the conjugated system (delocalization of the electrons). Where nitrogen is the heteroatom, this differ-
ence can be expressed by the designation pyridine-like N-atom Qr pyrrole-like N-atom.

• Heteroaromatic systems
This includes heteroannulenes, which comply with the HÜCKEL rule, i.e. which possess (4n + 2)
^•-electrons delocalized over the ring. The most important group of these compounds derives from
[6]annulene (benzene). They are known as heteroarenes, e.g. furan, thiophene, pyrrole, pyridine, and
the pyrylium and thiinium ions. As regards stability and reactivity, they can be compared to the corre-
sponding benzenoid compounds [1].
The antiaromatic systems, i.e. systems possessing 4n delocalized electrons, e.g. oxepin, azepine, thi-
epin, azocine, and 1,3-diazocine, as well as the corresponding annulenes, are, by contrast, much less
stable and very reactive.
The classification of heterocycles as heterocycloalkanes, heterocycloalkenes, heteroannulenes and
heteroaromatics allows an estimation of their stability and reactivity. In some cases, this can also be
applied to inorganic heterocycles. For instance, borazine (see p 1), a colourless liquid, bp 55°C, is clas-
sified as a heteroaromatic system.

[1] P. v. Rague Schleyer, H. Jiao, Pure AppL Chem. 1996, 68, 209;
Chem.Rev. 2001,707, 1115;
C. W. Bird, Tetrahedron 1998, 54, 10179;
T. M. Krygowski, M. K. Cyranski, Z. Czarnocki, G. Häfelinger,
A. R. Katritzky, Tetrahedron 2000, 56, 1783.