The Chemistry of Heterocycles: Nomenclature and Chemistry of Three to Five Membered Heterocycles

By Vishnu Ji Ram, Arun Sethi, Mahendra Nath and Ramendra Pratap

Heterocycles are ubiquitously present in nature and occupy a unique place in organic chemistry as they are part of the DNA and haemoglobin that make life possible. The Chemistry of Heterocycles covers an introduction to the topic, followed by a chapter on the nomenclature of all classes of isolated, fused and polycyclic heterocycles. The third chapter delineates the highly strained three membered N,O and S containing aromatic and non-aromatic heterocycles with one and more than one similar and dissimilar heteroatom. The four-membered heterocycles are abundantly present in various natural and synthetic products of pharmacological importance. This chapter describes the natural abundance, synthesis, chemical reactivity, structural features and their medicinal importance. This class of compounds are present as sub-structures in penicillin and cytotoxic Taxol. Lastly, a chapter on the natural abundance, synthesis, chemical reactivity and pharmacological importance of 5-membered heterocycles with N,O,S heteroatom is covered. The chemistry of heterocycles with mixed heteroatom such as, N-S, N-O, N-S etc. is also described.

• Gives in-depth, clear information about various systems of nomenclature along with widely acceptable IUPAC system for naming various classes of heterocycles
• Provides complete information about natural occurrences, synthesis, chemical reactivity, pharmacological importance of heterocycles and their application in material science
• Highly relevant for graduate students and researchers, providing updated information about various isolated and fused N,O and,S containing heterocycles

• Language: English
• Publisher: Elsevier Science
• Release date: Jun 5, 2019
• ISBN: 9780081011911

Vishnu Ji Ram

Further to his superannuation as Dy. Director for the Central Drug Research Institute, Lucknow, UP, India, a world class, premier research Institute for drug development, Prof Ram became Emeritus professor and served various academic institutions for 10 years. Besides research experience, he has also earned 18 years of experience teaching heterocyclic chemistry to graduate and post-graduate classes. He has 256 publications to his name, including several review articles published in top chemistry journals. He is also recipient of prestigious fellowships from JSPS, Japan, Alexander von Humboldt (AvH), Germany and NIH, USA.

Book preview

The Chemistry of Heterocycles

Nomenclature and Chemistry of Three-to-Five Membered Heterocycles

First Edition

Vishnu Ji Ram

Arun Sethi

Mahendra Nath

Ramendra Pratap

Table of Contents

Cover image

Title page

Copyright

Dedication

Preface

Abbreviations

Chapter 1: Introduction

Abstract

Chapter 2: Nomenclature of Diverse Heterocycles

Abstract

2.1 Hantzsch-Widman Nomenclature

2.2 IUPAC Nomenclature

2.3 Fused Heterocyclic System

2.4 Trivial Names

2.5 Multiplicative Names in Fused Heterocyclic Systems

2.6 Replacement Nomenclature (a Nomenclature)

2.7 Bridged Heterocycles

2.8 Spiro Heterocycles

2.9 Systematic Names of Certain Polycyclic Heterocycles

Chapter 3: Three-Membered Ring Heterocycles

Abstract

3.1 Structural and Reactivity Aspects

3.2 Importance in Natural Products, Medicine, and Materials

3.3 Three-Membered Mononitrogen Heterocycles

3.4 Three-Membered Oxygen Heterocycles

3.5 Three-Membered Sulfur Heterocycles

3.6 Three-Membered Heterocycles With Two Mixed Heteroatoms

Chapter 4: Four-Membered Heterocycles

Abstract

4.1 Structural and Reactivity Aspects

4.2 Importance in Natural Products, Medicines, and Materials

4.3 Four-Membered Nitrogen Heterocycles

4.4 Four-Membered Oxygen Heterocycles

4.5 Four-Membered Sulfur Heterocycles

4.6 Four-Membered Heterocycles With Mixed Heteroatoms

Chapter 5: Five-Membered Heterocycles

Abstract

5.1 Structural and Reactivity Aspects

5.2 Importance in Natural Products, Medicines, and Materials

5.3 Five-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen One Oxygen (Fig. 7)

5.4 Five-Membered Isolated and Fused Heterocycles With an Oxygen Atom

5.5 Five Membered Isolated and Benzo-Fused Heterocycles With One Sulfur Atom

5.6 Five Membered Isolated and Benzo-Fused Heterocycles With Two Nitrogen Atoms

5.7 Five Membered Heterocycles With Two Sulfur Atoms

5.8 Five Membered Isolated and Benzo-Fused Heterocycles With Three or More Nitrogen Atoms

5.9 Five-Membered Isolated and Benzo-Fused Heterocycles With Two Mixed Heteroatoms

5.10 Five-Membered Heterocycles With Three Mixed Heteroatoms

Index

Copyright

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Dedication

This book is dedicated to the late Prof. R.P. Rastogi, Ex-Vice Chancellor, Banaras Hindu University, Varanasi, India, who was not only a mentor but also a continuous source of inspiration and encouragement.

Prof. R.P. Rastogi

Preface

Vishnu Ji Ram

Heterocycles constitute the largest segment of the most varied family of organic compounds with natural abundance of pharmacological importance. Regardless of the structure and functionality of carbocycles, heterocycles are formed by replacement of one or more than one carbons by similar or dissimilar heteroatoms. Mere introduction of heteroatoms in the carbocycles plays a significant role in their chemistry and pharmacological profiles. Out of nearly 12.5 million registered compounds, more than 80% of clinically used drugs belong to the heterocyclic ring system.

This book is mainly restricted to three- to five-membered heterocycles with the most common heteroatoms of nitrogen, oxygen, and sulfur heteroatom. These heterocycles are not only monocyclic but also benzo fused, such as indole, benzofuran, benzothiophene, benzothiazole, indazine, etc.

This book is comprised of 5 chapters. The first chapter is an introduction, while the second chapter is devoted to the nomenclature of various classes of heterocycles. There are mainly three ways to name heterocyclic compounds: (1) trivial nomenclature, (2) Hantzsch and Widman nomenclature, and (3) the International Union of Pure and Applied Chemists (IUPAC) system of nomenclature. The IUPAC system is widely used and universally accepted to name various classes such as bridged, spiro, and fused heterocycles considering preframed certain rules to avoid any duplicity.

Chapters 3–5 are devoted to the chemistry, structural aspects, and diverse applications of various classes of heterocycles with similar and dissimilar heteroatoms of nitrogen, oxygen, and sulfur in mono-, bi-, and polycyclic ring systems.

We are thankful to Dr. Abhinav Kumar, Department of Chemistry, Lucknow University, for providing electrostatic potential maps of numerous compounds. I wish to thank all authors Prof. Arun Sethi, Prof. Mahendra Nath and Dr. Ramendra Pratap for their participation and contribution in this book. Finally, I would like to thank my family for their support and patience.

Abbreviations

Ac2O acetic anhydride

AcOH acetic acid

CAN ceric ammonium nitrate

D Debye (unit for dipole moment)

DCM dichloromethane

DDT dichlorodiphenyltrichloroethane

DES Dess-Martin periodinane

DMA dimethylacetamide

DMAD dimethyl acetylenedicarboxylate

DME dimethoxyethane

DMF dimethylformamide

DMSO dimethyl sulfoxide

DPPP 1,3-bis(diphenylphosphino)propane

ESP electrostatic potential

FDA Food and Drug Administration

FVP flash vacuum pyrolysis

HMGA 3-hydroxy-3-methylglutaric acid

LAH lithium aluminum hydride

LUMO lowest unoccupied molecular orbital

m-CPBA m-chloroperoxybenzoic acid

N-BOC N-tert-butoxycarbonyl

NBS N-bromosuccinamide

NMP N-methylpyrrolidene

PMP polymethylpentene

PTSA p-toluenesulfonic acid

TBHP tert-butyl hydroperoxide

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

TMEDA tetramethylenediamine

Chapter 1

Introduction

Abstract

This chapter provides preliminary information about various organic and inorganic heterocycles. The compounds formed by insertion of one or more, similar or dissimilar heteroatoms in different cyclic systems are known as heterocycles. However, cyclic systems with atoms of same elements are known as isocyclic compounds such as Pentathiolane, pentazole, and benzene.

Keywords

Heterocycles; Pentathiolane; Pentazole; Silazene; Pyrrole; Pyridine

Cyclic compounds obtainable by insertion of one or more similar or dissimilar heteroatoms (other than carbon) in a carbocyclic system are designated as heterocyclic compounds. However, cyclic systems comprised of atoms of the same element are known as isocyclic compounds. Pentathiolane, pentazole, and benzene are the best examples of an isocyclic system, where sulfur, nitrogen, and carbon atoms are part of the three different cyclic systems.

Cyclic compounds comprised of more than one heteroatoms without carbon are designated as inorganic heterocyclic compounds. 1,3,5,2,4,6-Triazaborinane and silazene¹,² are the best examples of inorganic heterocyclic compounds.

Nitrogen, oxygen, and sulfur are the most common heteroatoms present either alone or together in a cyclic system. In fact, five- and six-membered heterocyclic compounds are widely present as isolated form or part of the fused ring systems of natural and synthetic origin. However, heterocycles with other heteroatoms such as As, Ag, Bi, Sb, Se, Te, Pb, B, etc. are also known but not very common. Of more than 21 million registered organic compounds, more than half are heterocycles either from synthetic or natural product origin. The stability and reactivity of the heterocycles depend on the ring strain as well as a degree of unsaturation of the ring system.

The electronic configuration of the heteroatom and ring strain in a heterocyclic system plays a significant role in their physical, chemical, and biological properties. Numerous mono-, di-, and polycyclic heterocycles in the form of isolated and fused ring systems are reported in the literature from natural and nonnatural resources. A large number of heterocyclic compounds such as alkaloids, antibiotics, essential amino acids, vitamins, hemoglobin, hormones, and synthetic drugs and dyes are essential to life. Nucleic acids are among those heterocycles known for carrying genetic information controlling inheritance. These nucleic acids are long chains of pyrimidine and purine bases held together by other types of materials. Numerous, naturally occurring pigments, fungicides, pesticides, herbicides, dyes, and plastics are heterocyclic compounds. More than 70% of the pharmaceuticals in clinical use belong to heterocyclic systems.

Insertion of heteroatoms in a carbocyclic framework enhances the bioavailability of the molecule due to higher electronegativity of the heteroatom compared to carbon, and thereby displays significant increased biodynamic properties. Nitrogen heterocycles are abundantly distributed in nature and many of them are also present as subunits in various natural products and display diverse pharmacological activities.

The significant contributions of heterocycles as agrochemicals, pharmaceuticals, imaging agents, pheromones, catalysts, and polymers have made them popular among other classes of organic compounds and play a pivotal role in taking the initiative for further investigation to obtain molecules of great significance for humankind and industry.

Heterocyclic compounds are mainly classified into three classes: fully saturated, partially saturated, and fully unsaturated. The saturated heterocycles, such as pyrrolidine, piperidine, etc., behave like aliphatic amines. All the carbons and heteroatoms in the saturated heterocycles are sp³ hybridized and the lone pair of electrons present is in nonbonded hybrid orbital. However, in unsaturated heterocycles, such as pyrrole, furan, and thiophene, all the atoms are sp² hybridized, and the lone pair of electrons of the heteroatom is either in "p" orbital or sp² hybridized orbital and contributes to an aromatic π electron sextet, responsible for their aromatic character. In the case of fully unsaturated conjugated heterocycles, all the carbons are sp² hybridized; the "p" orbital is perpendicular to the hybrid orbital and participates in π-bond formation. These heterocycles possess aromatic character because they fulfill the criteria of (4n + 2)π electrons for aromaticity. In the case of partially saturated heterocycles, all the carbons are sp³ hybridized except olefinic carbons, which are sp² hybridized. However, the sp³ state of hybridization of heteroatoms remains unchanged. The presence of partial unsaturation reduces the basicity of the molecule compared to fully saturated heterocycles because the electronegativity of sp² orbitals is higher compared to sp³ hybrid orbitals.

The smallest heterocyclic ring is comprised of three atoms, which may be saturated or unsaturated with one and more than one similar or dissimilar heteroatoms. The chemistry of this class of heterocyclic compounds is very interesting due to the ring strain caused by compression of bond angles that make them very reactive. The ring strain energy of saturated three-membered heterocycles such as aziridine, oxirane, and thiirane are 58.6, 54.4, and 37.7 kJ/mol, respectively. The unfavorable ring strain is not very apparent because its synthesis is relatively easy as a result of coming close to both ends of the three members intermediate for cyclization.

Pyrrolidine, a fully saturated five-membered nitrogen heterocycle, behaves as a heteroalicyclic amine with a dipole moment of 1.57 D and a pKa of ~ 36. However, pyrrole in an unsaturated five-membered heterocycle is a weak base with a pKa of ~ 17 but slightly higher dipole moment of 1.8 D compared to pyrrolidine. The electrostatic potential surfaces of pyrrolidine and pyrrole reveal the electronic distribution over all the molecules, and their dipole moments are in opposite directions (Fig. 1).

Fig. 1 Electrostatic potential surfaces of pyrrolidine and pyrrole.

The other monocyclic heterocycles, such as furan and thiophene, have a second lone pair of electrons, which are not part of the π orbital but are part of the sp² hybrid orbital. The resonance energy of pyrrole, furan, and thiophene is not as high as the cyclopentadienyl anion. However, the least electronegativity of sulfur enhances the resonance energy of thiophene as compared to pyrrole and furan.³

A simple six-membered conjugated unsaturated heterocycle, derived by replacing one of the CH groups of benzene with nitrogen, is known as pyridine. All the carbons as well as nitrogen in the pyridine are sp² hybridized. The lone pair of electrons in nitrogen in pyridine occupies sp² hybrid orbital. However, the π orbital, which is perpendicular on the sp² hybrid orbital, participates in π-bond formation. The lone pair of electrons of nitrogen does not participate in the aromatic sextet and thus it is π-deficient. The pKa of pyridine is 5.16 and its fully saturated analog, piperidine, has a pKa of 11.12 and a dipole moment of 1.17 D. The dipole moment of pyridine is 2.2 D. The resonance energy and electrostatic potential map of pyridine demonstrates that electron-withdrawing nitrogen is the negative end of the dipole and undergoes various electrophilic substitution reactions. The electrostatic potential surfaces of pyridine display overall electron density distribution (Fig. 2).

Fig. 2 Electrostatic potential surfaces of pyridine.

References

1 Eicher T., Hauptmann S., Speicher A. The Chemistry of Heteocycles. Wiley-VCH GMBH & Co KGaA; 2003.1.

2 Parikh A.R., Parikh H., Khunt R. The Essence of Heterocyclic Chemistry. New Delhi: New Age International (P) Limited, Publisher; 2013.2.

3 Bruice P.Y. Organic Chemistry. 5th ed. Upper Saddle River, NJ, USA: Pearson Prentice Hall, Pearson Education, Inc; 2007.955.

Chapter 2

Nomenclature of Diverse Heterocycles

Abstract

This chapter is entirely devoted on the nomenclature of various monocyclic, bicyclic, tricyclic, and polycyclic, including ortho-fused, ortho-peri-fused, bridged, and spiro, heterocycles with one or more similar or dissimilar heteroatoms present in the cyclic system. In heterocyclic chemistry every heterocyclic system has a special name, while individual compounds are named also by a trivial name based on their origin of occurrence or on their special properties. Hantzsch and Widman introduced methods for naming the five- and six-membered heterocycles, which later on extended to saturated, unsaturated, and other ring sizes of heterocyclic compounds. In this system an appropriate prefix is used for heteroatoms and their ring size. The stem ol (ole) has been used in the case of five-membered heterocycles, while the in (ine) stem is used for six-membered heterocycles. Difficulties arose in naming some ortho or ortho-peri-fused, bridged, and spiro heterocyclic ring systems by the Hantsch-Widman nomenclature, and a set of rules were framed for systematic names of such heterocycles by the International Union of Pure and Applied Chemistry, which is used most frequently worldwide. Replacement nomenclature, also known as a nomenclature, has been used to name the heterocyclic compounds in which prefixes end with a and the position and prefix for each heteroatom precede the name of corresponding hydrocarbons.

Keywords

Hantzsch-Widman nomenclature; IUPAC system of nomenclature; Trivial nomenclature; Replacement nomenclature; Methods to name fused; Bridged and spiro heterocycles

In heterocyclic chemistry, every heterocyclic ring system has a special name, while each individual compound has a trivial name originating from their occurrence. The systematic name of various heterocycles is based on their ring size, type of heteroatom, and nature of the ring whether it is saturated, partially saturated, or fully unsaturated. To make the task of nomenclature easy and satisfactory the International Union of Pure and Applied Chemistry (IUPAC) has formulated certain rules to systematize the naming of heterocyclic compounds.

2.1 Hantzsch-Widman Nomenclature

In 1887 and 1888, Hantzsch and Widman independently introduced methods for naming five- and six-membered mononitrogen heterocycles. Both approaches were based on the combination of appropriate prefixes, representing heteroatom and size of the ring. Initially, the stem ol (ole) was used for heteroatoms of oxygen, sulfur, selenium, and nitrogen of five-membered rings, while -in (-ine) was used for six-membered rings. Over the time, refinement and inevitable modification of initial proposals were made to keep the basic principle intact.

The system of nomenclature was extended to include rings of other sizes, additional heteroatoms, and the expression of various levels of hydrogenation. Stems were designated for all the various levels of saturated and unsaturated three-, four-, and five-membered rings. However, the stems for saturated and unsaturated 6- to 10-membered rings were also provided with appropriate prefixes depending on the presence of heteroatoms.

2.2 IUPAC Nomenclature

In 1957, the IUPAC Commission on Nomenclature for Heterocyclic Compounds codified the extension of the Hantzsch-Widman system as part of its rules. The heteroatoms to which the system applied were specified and certain exceptions and modifications were noted to avoid identical names already in use for entirely different compounds.

There are three considerations for the naming of a heterocycle:

1.Prefix for the heteroatom;

2.Ring size for 3- to 10-membered rings (stem);

3.Nature of the ring, whether saturated or unsaturated (suffix).

Thus monocyclic heterocycles are called:

Prefix + Stem + Suffix

Prefix:

1.This indicates the type of heteroatoms, their numbers and positions (Table 1).

Table 1

a Exceptions: when followed by in or ine, phospha becomes phosphor and arsa becomes arsen.

2.This also indicates when two or three similar or different heteroatoms are in a heterocyclic system.

3.When the heteroatoms are dissimilar, the citation begins with heteroatoms of a higher group in the periodic table with lower atomic number. The order of preferences is O > S > Se > N > P > Si, etc.

Stem:

This indicates the ring size from three to 10 members (Table 2).

Table 2

a Maximum number of noncumulative double bonds.

b Ete becomes etine and etene respectively and ole becomes oline and olene.

c Special prefixes is used for phosphorous, arsenic and antimony.

d The term -ane is not applicable for silicon, germanium, tin, and lead but perhydro term is used.

e Perhydro term is prefixed to the name of corresponding unsaturated compound.

Suffix:

a.This indicates the state of saturation or unsaturation and depends on the presence or absence of nitrogen and the ring size (Table 3):

Table 3

(i)In the case of fully saturated heterocycles the prefix perhydro is applied before the total name of the unsaturated state.

(ii)A suffix is not used.

(iii)A stem is not used.

(iv)In the case where the ring size is more than 10, the heteroatom is indicated by prefixes (Table 1: oxa, thia, aza, etc.) followed by the name of the monocarbocyclic ring.

Basic rules applicable under the IUPAC system of nomenclature for monocyclic heterocycles are:

B-1.2. Except four- and five-membered heterocycles, the maximum number of noncumulative double bonds is less than required, and the prefixes dihydro and tetrahydro, etc. are applied.

B-1.3. The prefixes di,, tri, tetra, etc. are applied to denote multiplicity of the same heteroatom.

B-1.4. In the presence of common heteroatoms in the cyclic system, the priority rule (oxygen, sulfur, nitrogen) for heteroatoms is followed during nomenclature.

B-1.51. The position of the single heteroatom decides the peripheral numbering of a monocyclic system.

B-1.53. In the presence of different heteroatoms in a cyclic system the priority rule for numbering of heteroatoms is applied and number 1 is given to it; the lowest locants are given to the other heteroatoms.

A heterocyclic system having a lesser degree of unsaturation than required and prefixed dihydro- or trihydro is used (Tables 4 and 5).

a.In heterocyclic systems having a substituent in the ring, a heteroatom is assigned number 1 and the substituent is given the lowest possible number.

Table 4

Table 5

compounds.

b.In a monoheterocyclic system the presence of the maximum number of noncumulative double bonds is regarded as a parent compound.

c.In the case of partial saturation the prefixes dihydro and tetrahydro are used depending on the number of saturated carbons.

d.Monocyclic heterocycles with two or more similar heteroatoms in the ring are named by combining appropriate Arabic numerical prefixes for the position and di, tri, tetra, etc. for the number of heteroatoms, with endings as in Table 2.

e.Heterocycles with two or more dissimilar heteroatoms are named by combining the appropriate prefix with the ending in Table 2 in order of their preference (O > S > Se > N, etc.). The numbering in such heterocycles starts from the heteroatom of high preference around the ring to give the smallest number to other heteroatoms.

f.Obligatory saturation at a single position is indicated by the symbol 1H, 2H, 3H, etc. in accordance with the position of saturated carbon atoms with respect to the heteroatom.

, is transformable to a carbonyl function, the hydrogen of that position is cited with a capital italic "H" in parentheses as evident from the examples.

h.If there are different arrangements for noncumulative double bonds in a heterocyclic ring, the position of saturated carbon is given the lowest possible Arabic number with an italic "H" followed by the name of the respective heterocycle.

2.3 Fused Heterocyclic System

When two or more than two cyclic ring systems, i.e., carbocyclic and heterocyclic or heterocyclic with another heterocyclic system, combine in such a way that each component has at least one common bond, then they are called fused heterocycles. For the nomenclature of such heterocycles, selection of the base component is essential. There are certain criteria for the selection of base components.

(i)Such heterocycles in which a carbocyclic ring is fused with a monoheterocyclic ring, the latter is selected as a base component. For naming such compounds the side of the ring is labeled with the italic letters a, b, c, d, e, f, etc. following the direction of numbering. Therefore side "a is positioned between 1,2 and side b" is positioned between 2,3, and so on, as shown here for pyridine.

The name of the fused carbocyclic ring is attached as a prefix with the ending o. In quinoline, benzene is fused with pyridine and is called benzo[b]pyridine.

In the absence of nitrogen, the ring containing heteroatom of highest priority (Table 1) is considered as the base component. The following are various examples of fused heterocycles with different sites of fusion.

(ii)When two heterocycles are fused with each other, the nitrogen-containing heterocycle is considered as the base component. In the following three classes of fused compounds, the pyridine ring is considered as the base component in their nomenclature.

(iii)The other criterion for selection of base components is based on the presence of heteroatoms of higher priority (other than nitrogen) in the fused heterocyclic ring.

(iv)Fused heterocycles with the largest ring size are selected as base components for the nomenclature. In the following examples, base component is a seven-membered oxepine ring and is used as a suffix.

(v)Heterocyclic compounds with the greatest number of rings are preferred for their base component over smaller rings for their nomenclature. In all the following examples, heterocycles with the greatest number of rings, chromene and carbazole, are preferred over pyran, thiopyran, and pyrazine rings.

(vi)When two heterocycles are fused together, the selection of base component is done on the basis of highest number of heteroatoms in the cyclic ring.

(vii)Heterocycles having a variety of heteroatoms are preferred for the selection of base component over rings having no variety of heteroatoms. In all the three examples, oxazole, thiazole, and thiazine rings are selected as base components due to a variety of heteroatoms and their names are used as suffixes.

(viii)In heterocycles in which both fused rings have the same number of similar heteroatoms with same ring size, the base component is that heterocycle in which heteroatoms are adjacent or close, as evident from the following examples.

The ring fused with the base component is known as the attach component and its name is used as a prefix by replacing terminal e with o with exceptions as shown here.

Determination of Sides of Fusion of Two Fused Heterocycles

The side of fusion of a parent ring is indicated by a letter of the alphabet, which is placed within square brackets at the end. The side of fusion of the prefix ring (attach component) is indicated by two numbers denoting the positions of fusion with the parent ring (base component) and is placed within the square brackets prior to the side of fusion of the parent ring. The order of writing these two numbers is followed in the direction of lettering of the parent ring.

(a)In peripheral numbering of fused heterocycles, the lowest number is given to the prior heteroatom (Table 1). However, most prior heteroatoms are not close to the fusion side and the other closest heteroatom after fusion must take the least possible numbering regardless of priority.

(b)The heteroatoms on the fusion point are numbered in sequence, while carbons at the fusion point are designated by the previous number accompanied by the letters a, b, c, etc. as evident from the following examples.

(c)Priority is given to the saturated atom while numbering without consideration of substituent priority in the ring.

(d)The numbering in a fused heterocyclic system begins from the atom adjacent to the bridgehead with the lowest number 1. In case of more than one heteroatom, the first appearing heteroatom has priority.

(e)In a polycyclic heterocyclic system the orientation of the molecule is kept in such a way that the greatest number of rings lies in a horizontal row and the remaining maximum ring is above right of the horizontal row.

(f)In the case where two or more possible orientations meet the requirements, only one of them, the one with the fewest rings in lowest left quadrant, is selected.

The numbering begins with the atom that is not involved in fusion, counting counterclockwise the position of the uppermost ring without counting angular positions.

(g)In the nomenclature of polycyclic fused heterocycles, where two square brackets are required, the prefixes for the point of fusion are indicated by primed and unprimed numbers. The unprimed numbers are given to rings attached directly to the base component.

In this structure the base component is imidazo[4,5-b]quinoxaline and the attached component is the pyridine ring; its point of fusion is indicated by unprimed numbers (1, 2). The following are further examples of fused polycyclic heterocycles.

2.4 Trivial Names

The names of numerous monocyclic, bicyclic, tricyclic, and various natural products of heterocyclic ring systems are not systematic but are based on their occurrence or specific characteristics. The trivial nomenclature of heterocycles does not provide any useful information related to their structure. The systematic names of these heterocycles are not commonly used and are still widely known by their trivial names. The broader use of trivial names of heterocycles in the chemical literature is accepted by IUPAC because of their simplicity. The following trivial names of nitrogen heterocycles are also used as base components in fusion nomenclature. In attached component prefixes the terminal e is changed to o, e.g., indole to indolo.

Monocyclic: Furan, pyrrole, pyrazole, oxazole, triazole, imidazole, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, pyran.

Bicyclic: Indole, isoindole, quinoline, isoquinoline, indazole, quinazoline, pteridine, purine, indolizine, coumarin.

Tricyclic: β-Carboline, carbazole, phenazine, phenothiazine, phenanthridine.

Natural products: Nicotine, atropine, cinchonine.

2.5 Multiplicative Names in Fused Heterocyclic Systems

There are numerous heterocycles formed by ortho or ortho and peri-fusion of a parent component and these are treated as multiparent systems and given a multiparent name. Multiparent compounds with three, five, seven, etc. rings are known as extended multiparent systems.

(a)In a multiparent system, the multiple fusion of the parent component is indicated by using the prefix di-, tri-, etc. (or bis-, tris-, etc.) depending on the number of parent rings involved in the fusion.

(b)In a multiparent system, there is a distinction between parent components: the second one is denoted by primed letters, the third by double primed letters, etc., and sets of locants are separated by a colon.

(c)In cases where a base component is fused to a central component as well as to another component, the lowest letters are attached to the central site.

(d)Ring systems fused to a base component are designated as primary components. However, any ring system (other than a base component) fused to a primary component is called a secondary component and fusion sites are denoted by double primed numerical locants.

2.6 Replacement Nomenclature (a Nomenclature)

The nomenclature of certain fused heterocycles fails to express all fusion sites between basic components with prime, second, and third ring components, etc. This situation arises when two or more components are fused to one another as well as to the base component.

In replacement nomenclature all prefixes end with a, therefore it is also known as a nomenclature. The position and prefix for each heteroatom precede the name of the corresponding hydrocarbon.

In replacement nomenclature the heterocycle’s name is transformed to the corresponding carbocycle’s name and the prefix denotes the position and name of the heteroatom, such as oxa, thia, aza, etc. The heteroatom is given the lowest possible number.

Monocyclic and fused heterocycles are also named by their replacement nomenclature.

1.Monocyclic heterocycles:

2.Fused heterocycles:

Fused heterocycles are named by prefixing a terms preceded by their locants to the name of the corresponding hydrocarbon. The position of heteroatoms does not affect the numbering of the hydrocarbon. A low number is assigned to the heteroatom of higher priority next to heteroatoms in order and then multiple bonds.

In the case of substituents in fused polycyclic heterocycles, the position and name of substituents precede the trivial name of the heterocycles.

In such heterocycles where a heteroatom is present in the cationic form, the heteroatoms are named by replacing oxa, thia, aza, etc. with oxonia, thionia, azonia, etc., with their position as a prefix followed by the name of the cationic hydrocarbon.

2.7 Bridged Heterocycles

When a polycyclic ring skeleton cannot be completely named as a fused ring system, the only way to name such a skeleton is by considering it as a bridged fused ring system.

The bridged heterocyclic systems with two or more common atoms are named by corresponding acyclic hydrocarbons preceded by the prefix bicyclo followed by a square bracket indicating the number of carbon atoms in each of the three bridges connecting the two tertiary carbons in descending order and separated by a full stop.

The following are various examples of bridged heterocycles with their nomenclature.

(i)Numbering starts from one of the bridgehead atoms and proceeds through the longest possible route to the second bridgehead atom.

(ii)The heteroatom is given a number as low as possible.

(iii)When there is a choice between heteroatom and multiple bonds, the heteroatom is preferred.

(iv)If there is comparison between heteroatoms, the preference of numbering is given according to Table 1.

2.8 Spiro Heterocycles

Heterocyclic compounds in which one or more rings are fused at a common point are known as spiro heterocycles and the common atom carbon is quaternary in nature and designated as a spiro atom. Depending on the number of common atoms, they are classified as monospiro, dispiro, and trispiro heterocycles.

Monospiro heterocycles are named using the prefix spiro to show normal alkane with same total number of skeletal atoms. The number of atoms in each ring (leaving the spiro atom) is indicated in ascending order by Arabic numbers, separated by a full stop within square brackets, and placed between the prefix spiro and the name of the hydrocarbon. The name of heteroatoms with their positions is prefixed prior to the prefix spiro as evident from the following examples.

(i)The numbering in spiro heterocycles begins from the ring atom of the smaller ring adjacent to spiro carbon and proceeds first around smaller ring atoms then around bigger rings through the spiro atom. The lowest possible numbers are assigned to heteroatoms. In the case of different heteroatoms, preferential numbering is decided on the basis of heteroatom priority (Table 1).

Different examples of spiro heterocycles with different heteroatoms are depicted in the following to explain the nomenclature.

(ii)Preference is given to the heterocyclic ring over the carbocyclic ring of the same size. In case both rings are heterocyclic, the preference is given to the ring that contains a heteroatom of higher priority (Table 1).

(iii)In case of unsaturation in the ring, the numbering pattern remains the same but the direction of counting of atoms around the ring is done in such a way to assign the least possible number to multiple bonds. However, the heteroatom is preferred over multiple bonds.

(iv)In the case when both the rings of a spiro heterocycle are a fused ring system, the names of both the components are cited after the prefix spiro in square brackets, in alphabetical order, and separated by the numbers of spiro atoms. The components in such a spiro heterocyclic system retain their numbering, but the second component is numbered by prime numbers.

(v)When both the heterocyclic components are the same in the spiro heterocyclic system, spirobi- is prefixed to the name of the heterocyclic component in square brackets.

2.9 Systematic Names of Certain Polycyclic Heterocycles

References

1 International Union of Pure and Applied Chemistry. Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H. Oxford: Pergamon Press; 1979.

2 Hantzsch A., Weber J.H. Ber. Dtsch. Chem. Ges.. 1887;20:3118.

3 Widman O. J. Prakt. Chem.. 1888;38:185.

4 McNaught A.D. Adv. Heterocycl. Chem.. 176. 1976;20.

5 Hale W.H. J. Am. Chem. Soc.. 1919;41:370.

6 Patterson A.M. J. Am. Chem. Soc.. 1938;50:3074.

7 A. M. Patterson, L. I. Capell, D. F.Walkker, The Ring Index, eds., Supplements, I, II, III, Am. Chem. Soc., 1959.

8 International Union of Pure and Applied Chemistry, 1966, Nomenclature of Organic Chemistry (1957), Sections A and B, 1st ed., Butterworths, London, 1958, 2nd ed., Butterworths, London, Table I, 51.

9 International Union of Pure and Applied Chemistry. Definitive Rules of Organic Chemistry. J. Am. Chem. Soc.. 1960;82:5545.

10 International Union of Pure and Applied Chemistry. Nomenclature of Organic Chemistry, Sections A and B, 3rd ed. and Section C. 2nd ed. London: Butterworths; 1971.

11 International Union of Pure and Applied Chemistry. Nomenclature of Organosilicon Compounds. In: Compt. Rend. Quinziène Conf., Amsterdam; 1949:127–132.

12 American Chemical Society, Report of the ACS Nomenclature, Spelling and Pronunciation Committee for the First Half of. F. Organosilicon Compounds. Chem. Eng. News. 1952;30:4517–4522.

13 Patterson, A. M.; Capell, L.T., Walker, D.F. The Ring Index, 2nd ed., American Chemical Society, Washington, D.C., 1960; Supplement I, 1963; Supplement II, 1964; Supplement III, 1965.

14 International Union of Pure and Applied Chemistry. Revision of the Extended Hantzsch-Widman System of Nomenclature for Heteromonocycles, Provisional Recommendations, 1978. Pure Appl. Chem.. 1979;51:1995.

Chapter 3

Three-Membered Ring Heterocycles

Abstract

In this chapter the chemistry and structural aspects of three-membered saturated and unsaturated nitrogen, oxygen, and sulfur heterocycles with monoheteroatoms such as aziridine, 1H-azirine, 2H-azirine, oxirane, oxirene, thiirane, thiirane-1,1-dioxide, thiirene, thiirene-1-oxide, and thirene-1,1-dioxide are described. Analogously the structural aspect and chemistry of saturated and unsaturated heterocycles with two similar heteroatoms such as diaziridine, diazirine, dioxirane, dithiirane, and with mixed heteroatoms such as oxaziridine, oxathiirane, and thiazirine are also delineated. The importance of these heterocycles in natural products, medicine, and material science has been introduced.

Keywords

Aziridine; Azirine; Diaziridine; Diazirine; Oxirane; Oxirene; Dioxirane; Thiirane; Dithiirane; Thiirane-1; 1-dioxide; Thiirene; Thiirene-1-oxide; Thirene-1; 1-dioxide; Oxaziridine; Oxathiirane; Thiazirine

Insertion of a heteroatom such as nitrogen, oxygen, sulfur, phosphorus, etc. in the cyclopropane and cyclopropene ring, replacing one of the carbons, produced a variety of three-membered saturated heterocycles such as aziridine, oxirane, thiirane, phosphirane, and their unsaturated counterparts azirine, oxirene, thiirene, phosphirene, etc. This change greatly affects the physical and chemical properties of the new molecules due to distortion in the bond angles and ring strain.

In saturated three-membered heterocycles, both the carbons and heteroatom are sp³ hybridized and the lone pair of nonbonding electrons on aziridine are in the orbital with more "s characters than for a typical amine. By decreasing bond angles in small ring heterocycles, the internal bonds possess more p characters, leaving external bonds with more s" character hybrid orbitals responsible for their basicity. However, in the case of unsaturated heterocycles, both carbons and heteroatoms are sp² hybridized and the "p orbital of each atom is perpendicular on hybrid orbitals. The greater s" character and higher electronegativity of sp² orbitals in unsaturated small ring heterocycles make them less basic.

3.1 Structural and Reactivity Aspects

It is a bare fact that in a cyclic system there is distortion in natural bond angles, which is more apparent as the size of the ring decreases causing bond angle strain in the ring.H in aziridine and oxirane are 114 and 116 degrees, respectively, which is almost intermediate between tetrahedral (109.5 degrees) and trigonal (120 degrees) configurations. The internal bond angle at the heteroatom in oxirane (61 degrees) is approximately close to aziridine, while in thiirane (48.5 degrees) it is lower and highly compressed, producing strain in the ring. The reduced rate of pyramidal inversion in nitrogen is another important property of aziridines. The energy barrier for nitrogen inversion (∆ G ≈ 17 kcal/mol) is quite high as compared to aliphatic amine [∆ G ≈ 6 kcal/mol] because of increased bond angle strain.

Induction of a double bond in three-membered saturated heterocycles such as 2H-azirenes further increases the distortion in bond angles, which makes them more reactive and less basic. The strain is calculated based on experimental and estimated enthalpies of formation. The ring strain energy calculated using ab initio molecular orbital methods for 1H-azirine is 33–37 kcal/mol higher than 2H-azirine. Thus 1H-azirine is more basic compared to aziridine as well as 2H-azirine.

The highly strained three-membered ring of 2H-azirine is responsible for various ring-opening reactions, while the presence of a double bond is another reactive site for nucleophilic addition as well as cycloaddition reactions.

The bond lengths, bond angles, and bond strain energy of aziridine, oxirane, and thiirane are mentioned in C bond lengths revealed that the bond is short in length compared to normal