NTA Level 5 • Semester 1 • PST05106

Introduction to Heterocyclic Compounds

Pharmaceutical Organic Chemistry • Source Session/Topic 23

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Session 23: Introduction to Heterocyclic Compounds.

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

By the end of this session students are expected to be able to:

• Define heterocyclic compounds

• Classify heterocyclic compounds

• Explain nomenclature of heterocyclic compounds

• Draw chemical structure of heterocyclic compounds

Resources Needed:

• Flip charts, marker pens, and masking tape.

• Black/white board and chalk/whiteboard markers.

SESSION OVERVIEW

SESSION CONTENTS.

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes).

READ or ASK students to read the learning tasks and clarify.

ASK students if they have any questions before continuing.

STEP 2: Definition of Heterocyclic Compounds (10minutes).

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are Heterocyclic compounds? |

| |

|ALLOW few students to respond. |

| |

|WRITE their responses on the flip chart/ board. |

| |

|CLARIFY and SUMMARISE by using the content below |

• Heterocyclic compound, also called heterocycle, any of a major class of

organic chemical compounds characterized by the fact that some or all of

the atoms in their molecules are joined in rings containing at least one

atom of an element other than carbon (C).

• The cyclic part (from Greek kyklos, meaning “circle”) of heterocyclic

indicates that at least one ring structure is present in such a compound,

while the prefix hetero- (from Greek heteros, meaning “other” or

“different”) refers to the noncarbon atoms, or heteroatoms, in the ring.

• Heterocyclic compounds include many of the biochemical material essential

to life. For example, nucleic acids, pigments, vitamins, and antibiotics.

STEP 3: Classification of Heterocyclic Compounds (25 minutes).

• Classification of heterocyclic compounds depends on ring size because

heterocyclic rings of a given size has many common features.

• Therefore, heterocyclic compounds can be classified as:

o Three-membered rings

o four-membered rings

o Five-membered rings

o six-membered rings

o Seven-membered rings

• Three-membered rings

o The three-membered ring heterocycles containing single atoms of

nitrogen, oxygen, and sulfur—aziridine, oxirane (or ethylene oxide),

and thiirane, respectively—and their derivatives can all be prepared

by nucleophilic reactions, of the type shown.

o Thus, aziridine is formed by heating β-aminoethyl hydrogen sulfate

with a base (in this case Y is −OSO3H).

[pic]

• Four-membered rings

o Azetidine, oxetane, and thietane—four-membered rings containing,

respectively, one nitrogen, oxygen, or sulfur atom—are prepared by

nucleophilic displacement reactions similar to those used to prepare

the corresponding three-membered rings.

[pic]

• Five-membered rings with one heteroatom

o The parent aromatic compounds of this family—pyrrole, furan, and

thiophene—have the structures shown.

[pic]

o The saturated derivatives are called pyrrolidine, tetrahydrofuran, and

thiophane, respectively.

o The bicyclic compounds made of a pyrrole, furan, or thiophene ring

fused to a benzene ring are called indole (or isoindole), benzofuran,

and benzothiophene, respectively.

• Six-membered rings with one heteroatom

o The nomenclature used for the various monocyclic nitrogen-containing

six-membered ring compounds is given below.

o Positions on the ring are shown for pyridine, Arabic numerals being

preferred to Greek letters, although both systems are used.

o The pyridones are aromatic compounds because of contributions to the

resonance hybrid from charged resonance forms such as that shown for 4-

pyridone.

[pic]

STEP 4: Nomenclature of Heterocyclic Compounds (30 minutes).

• Many heterocycles, especially amines, were identified early on, and

received trivial names which are still preferred.

• Some monocyclic compounds of this kind are shown in the following chart,

with the common (trivial) name in bold and a systematic name based on the

Hantzsch-Widman system given beneath it in blue.

[pic]

• An easy to remember, but limited, nomenclature system makes use of an

elemental prefix for the heteroatom followed by the appropriate

carbocyclic name.

• A short list of some common prefixes is given in the following table,

priority order increasing from right to left.

• Examples of this nomenclature are: ethylene oxide = oxacyclopropane,

furan = oxacyclopenta-2,4-diene, pyridine = azabenzene, and morpholine =

1-oxa-4-azacyclohexane.

| | |r |m |n |s |on | |

|Valence|II |II |II |III |III |IV |III |

| | | | | | | | |

• The Hantzsch-Widman system provides a more systematic method of naming

heterocyclic compounds that is not dependent on prior carbocyclic names.

• It makes use of the same hetero atom prefix defined above (dropping the

final "a"), followed by a suffix designating ring size and saturation.

• As outlined in the following table, each suffix consists of a ring size

root (blue) and an ending intended to designate the degree of

unsaturation in the ring.

• In this respect, it is important to recognize that the saturated suffix

applies only to completely saturated ring systems, and the unsaturated

suffix applies to rings incorporating the maximum number of non-cumulated

double bonds.

• Systems having a lesser degree of unsaturation require an appropriate

prefix, such as "dihydro"or "tetrahydro".

|Ring Size |3 |4 |5 |6 |7 |8 |9 |10 |

| Saturated|iran|e |e | | | | | |

| |e | | | | | | | |

• Despite the general systematic structure of the Hantzsch-Widman system,

several exceptions and modifications have been incorporated to

accommodate conflicts with prior usage.

• Some examples are:

o The terminal "e" in the suffix is optional though recommended.

o Saturated 3, 4 & 5-membered nitrogen heterocycles should use

respectively the traditional "iridine", "etidine" & "olidine"

suffix.

o Unsaturated nitrogen 3-membered heterocycles may use the

traditional "irine" suffix.

o Consistent use of "etine" and "oline" as a suffix for 4 & 5-

membered unsaturated heterocycles is prevented by their former use

for similar sized nitrogen heterocycles.

o Established use of oxine, azine and silane for other compounds or

functions prohibits their use for pyran, pyridine and

silacyclohexane respectively.

• Examples of these nomenclature rules are written in blue, both in the

previous diagram and that shown below.

• Note that when a maximally unsaturated ring includes a saturated atom,

its location may be designated by a "#H " prefix to avoid ambiguity, as

in pyran and pyrrole above and several examples below.

• When numbering a ring with more than one heteroatom, the highest priority

atom is #1 and continues in the direction that gives the next priority

atom the lowest number.

[pic]

• All the previous examples have been monocyclic compounds. Polycyclic

compounds incorporating one or more heterocyclic rings are well known.

• A few of these are shown in the following diagram.

• As before, common names are in black and systematic names in blue.

• The two quinolines illustrate another nuance of heterocyclic

nomenclature.

• Thus, the location of a fused ring may be indicated by a lowercase letter

which designates the edge of the heterocyclic ring involved in the

fusion, as shown by the pyridine ring in the green shaded box.

[pic]

• Heterocyclic rings are found in many naturally occurring compounds.

• Most notably, they compose the core structures of mono and

polysaccharides, and the four DNA bases that establish the genetic code.

STEP 5: Chemical Structure of Heterocyclic Compounds (30 minutes).

• Three- and four-membered rings, because of their small size, are

geometrically strained and thus readily opened; they are also readily

formed.

o Such heterocycles are well-known reactive intermediates.

• Five- and six-membered rings are readily formed and are very stable;

their sizes also allow the development of aromatic character.

• Seven-membered rings and larger are stable but less readily formed and

relatively less well investigated.

[pic]

STEP 6: Key Points (10 minutes)

• A heterocyclic compound or ring structure is a cyclic compound that

has atoms of at least two different elements as members of its

ring(s).

• Heterocyclic compounds are classified based on ring size because

heterocyclic rings of a given size have many common features.

• The Hantzsch-Widman system provides a more systematic method of naming

heterocyclic compounds that is not dependent on prior carbocyclic

names.

• Three- and four-membered rings, are geometrically strained because of

their small size, and thus readily opened.

STEP 7: Evaluation (10 minutes)

• What are heterocyclic compounds?

• Classify heterocyclic compounds.

• Name three heterocyclic compounds using Hantzsch-Widman system.

• Draw three chemical structure of heterocyclic compounds.

References

Ternay, A.L (1976). Contemporary Organic Chemistry. Philadelphia, United

States: W.B. Saunders Co.

Morrison R.T and Boyd R N (1997). Organic Chemistry (6th Ed.). New Delhi,

India: Prentice Hall of India

Graham Solomon et al (2014). Organic Chemistry (11th Ed.). New Jeysey,

United States: John Willey and Sons.

Nadendla R. R. (2005). Principles of Pharmaceutical Organic Chemistry. New

Delhi, India: MacMillan Publishers

Bruice Y (2013). Organic Chemistry (7th ed.). New York, United States:

Prentice Hall Pearson.

Delgado J. N. Et al (1998). Wilson and Gisvold's Textbook of Organic

Medicinal and Pharmaceutical Chemistry (10th Ed.). California, United

States: Lippincott Williams

Bhassin S.K, Gupta R.(2013). Pharmaceutical organic chemistry (E-book

Kindle edition). New Delhi, India: Elsevier Publishing Services

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