National University –SUDA Faculty of Clinical and Industrial Pharmacy

Second Year (Batch-PA-14)-Semester Four

Organic Chemistry in Pharmacy

Course Coordinator: Us. Ghada Mustafa Eltayeb,

Phone Number (00249-912242444 / 00249-990997710).

Assistant Coordinator: Us. Maria Elamin Hamid,

Phone Number (00249-913714903 )

Heterocyclic Compounds

To identify heterocyclic compounds

Nomenclature of heterocyclic compounds

To study the fused ring systems

These are considered to be derived from the carbocyclic compounds by the replacement of one or more carbon atoms by the heteroatom(s) such as N, O, S etc.

In earlier days of organic chemistry, names were given to compounds as a means of identifying them, usually before their structure were known.

A systematic nomenclature is necessary so that the structure of the compound can be deduced from its name.

Several different systems of nomenclature have been devised for heterocyclic compounds.

The most systematic nomenclature so far devised is “Replacement Nomenclature”

But, normally, particularly for aromatic heterocycles, a hybrid of trivial and Hantzch-Widman systems is used.

These were given before their structural identification.

Trivial names of the heterocycles were given on the basis of their characteristic properties (or) on the sources from which they are obtained. Eg: Picoline, Furfurol, Pyrrole.

Therefore the trivial names hardly provide any structural information.

There are about 49 ‘recognized’ trivial names. Eg: Pyrole, Pyrazole, Pyran, Purine, Pyrimidine,

Quinoline, Isoquinoline, Xanthene, Perimidine.

The surviving trivial names are important because they are used as basis for constructing- more systematic,

names for derivatives (or) for polycyclic systems.

This is the most widely used systematic method and is used for naming three- to ten-membered heterocyclic systems with various degrees of unsaturation.

This nomenclature specifies the ring size, nature, type and position(s) of the heteroatom(s).

Trivial names eg: pyrrole, imidazole, pyridine must be preferred over the sytematic names.

For partially saturated heteromonocycles, the prefixes ‘dihydro’, ‘tetrahydro’ etc should be used.

Azine must not be used for pyridine because of its use as a class name of the compounds containing =N—N= group.

Ring Size

Unsatura

tion Saturation

Three irene(a) irane(b)

Four - ete etane(b)

Five- ole olane(b)

Six- A ine ane

B ine inane

C inine inane

Seven- epine epane

Eight- ocine ocane

Nine- onine onane

Ten- ecine ecane

Heteroatom Valence Prefix

Oxygen II Oxa

Sulfur II Thia

Selenium II Selena

Tellurium II Tellura

Nitrogen III Aza

Phosphorous III Phospha

Arsenic III Arsa

Antimony III Stiba

Bismuth III Bisma

Silicon IV Sila

Germanium IV Germa

Tin IV Stanna

Lead IV Plumba

Boron III Bora

Mercury II Mercura

Prefixes for heteroatoms

(decreasing order of priority)

The heteromonocyclic system is named by combining one or more ‘a’ prefixes for the heteroatom(s) with a stem indicating the size of the ring. If the stem begins with vowel, the terminal letter ‘a’ of the ‘a’ prefix is dropped.

Prefixes: The prefixes indicate the heteroatoms present in the heterocyclic systems. The prefixes for different heteroatoms are presented in the table in the order of preference.

Stems: The stems are used to indicate the size of the ring and the saturation/unsaturation in the heteromonocyclic systems.

When two or more heteroatoms of the same type are present, then the prefixes, di-, tri-, etc. are used and placed before the prefix used for the heteroatom.

•When two or more different heteroatoms are present in the same ring, the prefixes

of heteroatoms are combined in the order of preference.

With two or more identical heteroatoms: The ring is numbered in such a way

that the heteroatoms are assigned the lowest possible set of number of locants.

Numbering

With one heteroatom: The numbering starts from the heteroatom

giving the position-1 and proceeds in such a way as to give the lowest

possible locant to the substituent if present.

With two or more different heteroatoms: The numbering starts from the

heteroatom with the highest preference as in the table (O>S>N…). The

remaining heteroatoms are given lowest number locants.

When heterocyclic ring with maximum number of noncumulative double bonds contains a saturated atom, its position is given the lowest possible locant and is numerically indicated by an italic capital H before the name of heterocyclic ring system.

•However, the heterocyclic system in which a carbon atom of the ring is involved in the carbonyl group, the indicated hydrogen is normally cited as an italic capital H in parenthesis after the locant of the additional structural features.

FUSED RING

The fused heterocyclic system is considered to be constructed by the combination of two or more cyclic structural units.

The cyclic structural units contain maximum number of non-cumulative double bonds and are fused in such a way that each structural unit has one bond common with other.

Nitrogen containing component: a nitrogen containing component is selected as base component.

• If nitrogen is absent, then ring with other heteroatom(s) is selected as base

component (order of preference as in the table)

Component with greatest number of rings is selected and named with recognized

trivial name if possible.

• If rings of unequal size are present, then the one with largest size of the ring is selected.

• If rings or equal size with different number of heteroatoms are present, then the ring with greater number of heteroatoms of any kind is considered as a base component.

If rings of equal size with equal number of different heteroatoms arepresent, then the component containing ring with greatest variety ofheteroatoms is selected.

If two heteroatoms of the same group are present, then componentscontaining heteroatoms appearing first in table is preferred.

• If rings of same size with same numbers and same kinds of heteroatoms are

present, then the component containing the ring with heteroatoms which have

lowest locant numbers is preferred.

If a benzene is fused to the heterocyclic ring, the compound is named by placing number(s) indicating position(s) of the heteroatom(s) before the prefix benzo- (from benzene) followed by the name of the heterocyclic component.

However, the heterocyclic system in which two benzene rings are

orthofused to a six-membered 1,4-diheteromonocycle containing the

same heteroatoms are named by adding the replacement prefix for the

heteroatom to the term ‘-anthrene’ replacing ‘a’.

If two benzene rings are ortho-fused to a six membered1,4-dihetero monocyclic ring containing different atoms,then it is named by adding the prefix ‘pheno-’ to the H-Wname of heterocycle.

This system is based on the fact that the heterocylic compounds are derivatives of carbocyclic compounds. Therefore the rules of nomenclature are similar to those applied for the carbocyclic compounds.

It is used for the heterocycles containing unususal heteroatom(s), spiro- and bridged heterocyclic systems.

Monocyclic Heterocycles

Fused Heterocycles

Spiro Heterocycles

Bridged Heterocycles

Heterocyclic ring assemblies

The ring obtained from the heterocyclic compound by replacing heteroatom(s) by CH2, CH or C according to the valence of heteroatom(s) is named by IUPAC rules.

The type of heteroatom is indicated by the prefix (according to the table). Since all the prefixes end with the letter ‘a’ the replacement nomenclature is also known as ‘a’ nomenclature. The position and prefix for each heteroatom are placed before the name of the corresponding carbocyclic sytem.

• The replacement names derived from benzene are retained only if

three double bonds are present, otherwise the names with –ene, -

diene, etc as necessary are used.

The corresponding carbocyclic ring without maximum number of non-cumulative double bonds is named without using prefix for hydrogen atom. The ring is named in its state of hydrogenation.

• If the corresponding carbocyclic ring is without maximum number of non-

cumulative double binds, the heterocyclic system is considered to be with

maximum number of conjugated or isolated double bonds. The corresponding

carbocyclic ring is named as it contains maximum number of non-cumulative

double bonds.

The additional hydrogen atom, if present, is indicated by an italic capital ‘H’ with its position and placed before the position(s) and the prefix(es) of the heteroatom(s)

The compounds in which two rings are fused at a common point are known as spiro compounds and the common atom which is quaternary in nature is designated as spiro atom. They are classified according to the number of spiro atoms; monospiro-, dispiro-, trispiro- ring systems.

• Spiro heterocycles with one sprio atom consisting of one or both heterocyclic

rings are named by prefixing spiro to the name of normal alkane with same

number of carbon atoms. The number of atoms in each ring are indicated by

arabic numbers separated by a full stop and enclosed in a square bracket in

ascending order and are placed between spiro prefix and the name of

hydrocarbon. The heteroatoms are indicated by the prefixes and are prefixed with

their positions to the name of spiro hydrocarbon.

• The numbering starts from the ring atom of the smaller ring (if rings are of

unequal size) attached to the spiro atom and proceeds first around the smaller

ring and then around the larger ring through the spiro atom. The heteroatoms are

assigned the lowest possible number locants.

If there is a choice between two different heteroatoms, the preferential

numbering is decided according to the appearance of the heteroatoms in the

table.

• The heterocyclic ring is preferred over the carbocyclic ring of the same size. If both the rings are heterocyclic, the preference is given to the heterocyclic ring with the heteroatom appearing in the table.

If unsaturation is present in a ring, the pattern of numbering remains the same but the direction around the ring remains in such a way that the multiple bond is given number as low as possible. However, the heteroatom is preferred over the multiple bond.

• When one or both the components of spiro heterocycle are fused

polycyclic system, the names of both the components are cited after prefix

‘spiro’ in square bracket in alphabetical order and are separated by the

numbers of spiro atom. The components in such spiro heterocyclic system

retain their numbering, but the second component is numbered by primed

numbers.

]

If both the heterocyclic components are the same in spiro heterocyclic system, ‘spirobi-’ is prefixed to the name of heterocyclic component.

The bridged heterocyclic system consisting of two or more common atoms is given the name of acyclic hydrocarbon with the same total number of carbon atoms, which is preceded by the prefix ‘bicyclo-’ with the descending order of numbers separated by a full stop in square bracket indicating heteroatoms with their locants are prefixed to the name of bridged hydrocarbon.

The numbering starts from one of the bridgehead atoms and proceeds through the longest possible route to the second bridgehead atom and then by the second longest route to the first bridgehead atom and finally by shortest route from one bridgehead to the second bridgehead atom.

The heteroatom is given number as low as possible. When there is a choice, between heteroatom and multiple

bond, the heteroatom is preferred. If there is comparison between heteroatoms, the

preference of numbering is given according to the table and their prefixes with locants are arranged alphabetically.

Polycyclic bridged heterocycles are also named according to the rules adopted for bicyclic bridged heterocycles. However, the prefix tricyclo-, tetracyclo-, etc., depending on the number of rings is used.

The prefix (cyclo-) is followed by the numbers separated by full stops in square bracket in decreasing order indicating:

1. The number of atoms or two branches of the main ring containing maximum number of atoms.

2. The number of atoms in main bridge excluding bridgehead atoms and

3. The number of atoms in secondary bridges The location of each secondary bridge (the position of

bridgehead atoms involved in the secondary bridges) is indicated by superscripts to the numbers indicating its length and are separated by a comma.

The prefix (tricyclo-, etc.,) with numbers separated by full stop in square bracket is followed by the name of acyclic hydrocarbon if the carbon atoms equivalent to the total number of atoms in the bridged heterocyclic system.

The prefixes for the heteroatoms and the substituents with their positions are indicated and placed as usual.