Heterocyclic Chemistry, Chemistry tutorial


Compounds categorized as heterocyclic probably comprise the biggest and most varied family of the organic compounds. After all, each and every carbocyclic compound, in spite of structure and functionality, might in principle be transformed to a collection of heterocyclic analogs by substituting one or more of the ring carbon atoms by a different element. Even if we limit our consideration to oxygen, nitrogen and sulphur (the most general heterocyclic elements), the permutations and combinations of such a replacement are many.

The heterocyclic compound or ring structure is a cyclic compound which consists of atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the stream of chemistry dealing by the synthesis, properties and applications of such heterocycles. In contrary, the rings of homocyclic compounds entirely comprise of atoms of the similar element.

However heterocyclic compounds might be inorganic, most have at least one carbon. As atoms which are neither carbon nor hydrogen are generally termed to in organic chemistry as heteroatom, this is generally in comparison to the all-carbon backbone. However this doesn't prevent a compound like borazine (that consists of no carbon atoms) from being labeled 'heterocyclic'. IUPAC proposes the Hantzsch-Widman nomenclature for naming the heterocyclic compounds.

Heterocyclic compounds comprise most of the biochemical material necessary to life. For illustration, nucleic acids, the chemical substances which carry the genetic information controlling inheritance, comprise of long chains of heterocyclic units held altogether by other kinds of materials. Most of the naturally occurring pigments, vitamins and antibiotics are heterocyclic compounds, as are most hallucinogens. Modern society is reliant on synthetic heterocycles for use as drugs, pesticides, dyes and plastics.

Nomenclature of heterocyclic compounds:

Formulating a methodical nomenclature system for the heterocyclic compounds presented a formidable challenge that has not been uniformly concluded. Most of the heterocycles, particularly amines, were recognized early on and received trivial names that are still preferred. Some of the monocyclic compounds of this type are illustrated in the given chart, by the common (trivial) name in bold and a systematic name based on the Hantzsch-Widman system given below it in blue. For most of the students, learning such common names will give a sufficient nomenclature background.

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Fig: Nomenclature of heterocyclic compounds

A simple to keep in mind, however limited, nomenclature system makes use of the elemental prefix for the heteroatom followed by the suitable carbocyclic name. A short list of some common prefixes is provided in the given table, priority order increasing from right to left. Illustrations of this nomenclature are: ethylene oxide = oxacyclopropane, furan = oxacyclopenta-2,4-diene, pyridine = azabenzene, and morpholine = 1-oxa-4-azacyclohexane.

Element  oxygen    sulfur        selenium    nitrogen     phosphorous    silicon    boron

Valence     II             II               II               III                   III                 IV         III

Prefix       Oxa         Thia         Selena          Aza              Phospha          Sila       Bora

The Hantzsch-Widman system gives a more systematic process of naming heterocyclic compounds which is not based on prior carbocyclic names. This makes use of the similar hetero atom prefix stated above (that is, dropping the final 'a'), followed through a suffix designating ring size and saturation. As outlined in the given table, each and every suffix comprises of a ring size root (blue) and an ending intended to designate the degree of Unsaturation in the ring. In this respect, it is significant to recognize that the saturated suffix applies merely to fully 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 need a proper prefix, like 'dihydro' or 'tetrahydro'.

Ring Size         3          4            5        6        7            8          9         10


Unsaturated    irene     ete    ole     ine   epine    ocine    onine    ecine

Saturated        irane   etane olane inane epane    ocane   onane    ecane

In spite of the general systematic structure of the Hantzsch-Widman system, some of the exceptions and modifications have been incorporated to accommodate the conflicts by prior usage. Some illustrations are:

a) The terminal 'e' in the suffix is optional although recommended.

b) Saturated 3, 4 & 5-membered nitrogen heterocycles must make use of correspondingly the traditional 'iridine', 'etidine' and 'olidine' suffix.

c) Unsaturated nitrogen 3-membered heterocycles might use the traditional 'irine' suffix.

d) Consistent utilization of 'etine' and 'oline' as a suffix for 4 and 5-membered unsaturated heterocycles is prevented via their former utilization for similar sized nitrogen heterocycles.

e) Established utilization of oxine, azine and silane for other compounds or functions prohibits their utilization for pyran, pyridine and silacyclohexane correspondingly.

Heterocyclic rings are mainly found in most of the naturally occurring compounds. Most notably, they make up the core structures of mono and polysaccharides and the four DNA bases which establish the genetic code.

Main classes of heterocyclic compounds:

The main classes of heterocycles having the common heteroatoms - nitrogen, oxygen and sulphur are reviewed in order of increasing ring size, having compounds including other heteroatoms left to the final part. Categorization by ring size is convenient as heterocyclic rings of a given size encompass most of the general features. For heterocyclic (that is, as for carbocyclic) rings, certain broad generalizations can be formed. Three- and four-membered rings, due to their small size, are geometrically strained and therefore readily opened; they are as well readily formed. These heterocycles are well-known reactive intermediates. Five- and six-membered rings are readily made up and are very stable; their sizes as well allow the growth of aromatic character. Seven-membered rings and larger are stable however less readily formed and relatively less well investigated.

Three-membered rings:

The three-membered ring heterocycles having single atoms of nitrogen, oxygen, and sulphur -aziridine, oxirane (or ethylene oxide) and thiirane, correspondingly - and their derivatives can all be made up by nucleophilic reactions, of the type described. Therefore, aziridine is made up by heating β-aminoethyl hydrogen sulphate by a base (in this case Y is -OSO3H)

2322_Three-membered rings.jpg

Fig: Three-membered rings

A reaction of this kind is comprised in the pharmacological action of nitrogen mustards that were among the first anticancer drugs developed. Intramolecular ring closure, as in the case of anticancer agent mechlorethamine, generates an intermediate aziridinium ion, the biologically active agent that attacks quickly proliferating cells like cancer cells via inhibiting replication of their DNA (that is, deoxyribonucleic acid). Nitrogen mustards linked to steroids as well have been employed as anticancer agents.

Commercially, oxirane and (to a lesser level) aziridine are significant bulk industrial chemicals. Oxirane is made up on a large scale via the direct reaction of ethylene with oxygen.

Since 1950, 5 different classes of three-membered ring compounds having two heteroatoms have been discovered. They are derivatives of the parent ring systems diaziridine (having N-N), oxaziridine (O-N), thiaziridine (S-N), dioxirane (O-O), and dithiirane (S-S). The oxathiirane system has no reported stable representatives in its class.

Four-membered rings:

Azetidine, oxetane and thietane - four-membered rings containing, correspondingly, one nitrogen, oxygen or sulphur atom - are made up via nucleophilic displacement reactions identical to those employed to make up the corresponding three-membered rings.

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Fig: Four-membered rings

The most significant heterocycles having four-membered rings are two related series of antibiotics, the penicillin and the cephalosporins. Both series have the azetidinone ring (that is, the suffix -one pointing out an oxygen atom linked by a double bond to a ring carbon atom). The other common name for the azetidinone ring is the β-lactam ring that lends its name to the β-lactam antibiotics, the class to which the penicillin and cephalosporins belong. The chemistry of azetidinones was explored methodically throughout the intensive research into penicillin structure and synthesis that occur all through World War II. The practical synthesis of penicillin was not achieved, though, till the year 1959.

Many oxetanes, the synthetic analogs of the antiviral natural product oxetanocin, are under investigation as antifungal, anticancer, anti-inflammatory and antiviral agents. Oxetanones, whose ring structure is equivalent to that of the azetidinones apart from that the heteroatom is oxygen, are broadly applied in the polymer manufacturing and in agriculture as herbicides, fungicides and bactericides. The parent thietane was mainly found in shale oil, while its odoriferous derivatives function as scent markers for ferrets, minks and European polecats. Thietanes are utilized in the production of polymers, as bactericides and fungicides in paint and as iron corrosion inhibitors.

Five-membered rings with one heteroatom:

The parent aromatic compounds of this family - pyrrole, furan and thiophene - encompass the structures illustrated.

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Fig: Five-membered rings

The saturated derivatives are termed as pyrrolidine, tetrahydrofuran and thiophane correspondingly. The bicyclic compounds made up of a pyrrole, furan or thiophene ring fused to a benzene ring are known as indole (or isoindole), Benzofuran and benzothiophene, correspondingly.

The nitrogen heterocycle pyrrole takes place in bone oil, in which it is made up by the decomposition of proteins on strong heating. Pyrrole rings are mainly found in the amino acids proline and hydroxyproline, which are the components of numerous proteins and which are present in specifically high concentrations in collagen, the structural protein of bones, tendons, ligaments and skin.

The Pyrrole derivatives are well-known in the living world. Pyrrole compounds are mainly found among the alkaloids, a big class of alkaline organic nitrogen compounds produced mainly by plants. Nicotine is the best-known pyrrole-containing alkaloid. The heme group of oxygen-carrying protein hemoglobin and of related compounds like myoglobin; the chlorophylls, which are the light-gathering pigments of green plants and other photosynthetic organisms; and vitamin B12 are all made up from four pyrrole units joined in a larger ring system termed as a porphyrin, like that of chlorophyll.

The bile pigments are made up by the decomposition of porphyrin ring and have a chain of four pyrrole rings. Bilirubin, for instance, the brownish yellow pigment which provides feces its characteristic colour, is the end product of the breakdown of heme from destroyed red blood cells.

The phthalocyanines are a group of synthetic pigments which have four isoindole units linked altogether in a large ring. A typical member of the family is phthalocyanine blue (that is, Monastral Fast Blue).

Many compounds produced in animals or plants have one or more indole units in their molecular structure. The significant vat dye indigo, which comprises two indole units, has been employed for thousands of years and was formerly obtained from plants; however it is now synthesized on a large scale.

Tryptophan, an indole-containing necessary amino acid found in most of the proteins, is employed by the body to make some significant substances, comprising the neurotransmitter serotonin and the B-complex vitamin niacin (figure below illustrates Six-membered rings with one heteroatom). Skatole, a degradation product of tryptophan which retains the indole unit, contributes much of the strong odor of mammalian feces. Indole-3-acetic acid (heteroauxin or β-indolylacetic acid) are a plant-growth regulator and the most significant member of the Auxin family of plant hormones.

Most likely the best-known indole-containing compounds are the indole alkaloids that have been isolated from plants representing more than 30 families. The mushroom hallucinogens psilocin and psilocybin, the ergot fungus alkaloids, the drugs reserpine and yohimbine, and the poison strychnine all belong to this class or group.

The simplest member of furan family of oxygen heterocycles, furan itself, is transformed industrially via hydrogenation to tetrahydrofuran. Tetrahydrofuran is employed as a solvent and for the production of adipic acid and hexamethylenediamine, the raw materials for nylon-6,6, the most general form of nylon. The other furan derivatives of industrial significance are maleic anhydride and phthalic anhydride that are constituents of resins and plastics. Such compounds are made up in bulk via the oxidation of benzene and naphthalene, correspondingly.

All the carbohydrates, the biochemical family which comprises the sugars and starches, are composed of one or more simple sugar (that is, monosaccharide) units. These sugars are polyhydroxy aldehydes or polyhydroxy ketones which in aqueous solution exist as equilibrium mixtures of their open-chain and cyclized forms. Often the cyclized form of the sugar is a five-membered tetrahydrofuran ring known as a furanose, as illustrate below for fructose, or fruit sugar, as a cyclized isomer (known as a fructofuranose).

Six-membered rings with one heteroatom:

The nomenclature employed for the different monocyclic nitrogen-containing six-membered ring compounds is described below. Positions on the ring are illustrated for pyridine, Arabic numerals being favored to Greek letters, however both systems are employed. The pyridones are aromatic compounds due to contributions to the resonance hybrid from charged resonance forms like that described for 4-pyridone.

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Fig: Six-membered rings

Mono-, di- and trimethylpyridines - which is, pyridines having one, two or three attached methyl groups, correspondingly - are known as picolines, lutidines and collidines, correspondingly, by the position of the methyl groups denoted by numbers - example - 2,4,6-collidine. Pyridine-2-, -3- and -4-carboxylic acids as well have broadly employed trivial names: picolinic, nicotinic (that is, derived from nicotine, of which it is an oxidation product) and isonicotinic acid, correspondingly. Pyridine itself and the picolines, lutidines and collidines take place in coal tar and bone oil. The Pyridine derivatives are as well of great biological significance. For illustration, nicotinic acid is more generally termed as the B-complex vitamin niacin; a nutritionally equivalent form of niacin is nicotinamide or niacinamide. Pyridoxine is the other member of the B complex, vitamin B6.

The two coenzymes comprised in most of the significant metabolic reactions in living cells, nicotinamide adenine dinucleotide (NAD, as well termed as coenzyme I) and nicotine adenine dinucleotide phosphate (NADP, coenzyme II), are derived from the nicotinamide and the coenzyme pyridoxal phosphate (codecarboxylase) is a physiologically active form of pyridoxine.

Most of the alkaloids have a pyridine or piperidine ring structure, among them nicotine and piperine (that is, one of the sharp-tasting constituents of white and black pepper, from the plant species.

Pyridine that once was extracted commercially from coal tar however now is made up catalytically from tetrahydrofurfuryl alcohol and ammonia, is a significant solvent and intermediate employed to make other compounds.

Pharmaceutically significant pyridines comprise the tuberculostat isoniazid (that is, isonicotinic acid hydrazide), the anti-AIDS-virus drug nevirapine and the vasodilator nicorandil, employed for treating angina, the urinary-tract analgesic phenazopyridine, and the anti-inflammatory sulpha drug. 1-(1-phenylcyclohexyl) piperidine (PCP, phencyclidine) was initially employed as an anesthetic, however its powerful hallucinogenic properties have led to abuse. Diquat, paraquat, clopyralid, and diflufenican are renowned pyridine derivatives employed as herbicides.

Quinoline itself can be utilized to prepare nicotinic acid and other compounds like drugs and dyes. The production of synthetic quinoline far exceeds that from coal tar. Morphine, codeine, and thebaine - all having partially reduced isoquinoline rings - are alkaloids of the opium poppy and have been employed for most of the centuries as hypnotics and analgesics. The semisynthetic derivative of morphine, heroin, is an even more powerful hypnotic and a highly addictive drug.

Rings with seven or more members:

As the size of ring increases, the range of compounds which can be obtained via varying the number, kind, and location of the heteroatoms increases extremely. Nonetheless, the chemistry of heterocyclic compounds having rings seven-membered or larger is much less developed as compare to that of five- and six-membered ring heterocycles, however these compounds are generally stable and some of them have found practical application. Of the seven-membered ring compounds, one-heteroatom heterocycles - azepines, oxepines and thiepines and their derivatives are the most widely studied.

The increase in ring size constrains such compounds to be non-planar in order to lessen the ring strain. Nonplanarity, though, influences aromaticity, so such heterocycles react as cyclic polyenes (compounds having non-interacting, alternating single and double bonds). Azepine and oxepine rings are significant constituents of many naturally occurring alkaloids and metabolic products of the marine organisms. The azepine derivative caprolactam is made commercially in bulk for utilization as an intermediate in the preparation of nylon-6 and in production of films, coatings and synthetic leather. Seven-membered heterocycles having one or two nitrogen atoms in the ring are structural units of broadly employed psychopharmaceuticals like imipramine (trade name Prazepine) - the first of tricyclic antidepressants and the tranquilizer diazepam (that is, trade name Valium).

Of the larger ring heterocycles, the most significant are the crown ethers that have one or more heterocyclic rings including 12 or more ring atoms and comprising a number of different heteroatoms, generally nitrogen, oxygen or sulphur. The heteroatoms are generally separated via two-carbon or three-carbon units (that is, ethylene or propylene units, correspondingly). The first crown ether, dibenzo-18-crown-6, was synthesized in the year 1960.

The first number in a crown ether name points out the total number of atoms comprised in the macro cycle (that is, the large ring), while the second points out the number of heteroatoms in that ring. The remarkable characteristic of crown ethers that stimulated the explosive growth of their chemistry is their capability to selectively bind the ions of metal elements (example: potassium and sodium) and whole organic molecules within their cavities, the selectivity for a specific ion or molecule being directly associated to the size of the macro cycle. Due to this feature, crown ethers have found broad application as ion transporters, as materials for ion-selective electrodes employed in ecological testing for different metal ions, as sensitizers in photography, in medical diagnostics, and for the separation of radioactive isotopes.

However crown ethers are not found in nature, some of the larger ring heterocycles that have similar pronounced binding capabilities exist as natural products. An illustration is porphyrins, that are broadly distributed as biological pigments example: the magnesium-binding chlorophylls and the iron-binding heme groups of hemoglobin and myoglobin.

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