Most Influential Heterocycles In The World

Most Influential Heterocycles In The World Content Heterocyclic compounds ................................................................................................................... 1 Classification ..................................................................................................................................... 2 Preparation and reactions ................................................................................................................ 2 3-membered rings ..................................................................................................................... 2 Four-Membered Rings .............................................................................................................. 3 Reactions ........................................................................................................................................... 4 Heteroatom Saturated Unsaturated ......................................................................................... 5 Four-membered rings compounds with two heteroatoms ...................................................... 6 5-membered rings with a single heteroatom ........................................................................... 6 Five-membered rings compounds with a single heteroatom ................................................... 8 5-membered rings with 2 heteroatoms .................................................................................... 8 5-membered rings with 3 heteroatoms .................................................................................... 9 6-membered rings with 1 heteroatom ..................................................................................... 9 Pharmaceutically useful pyridines .................................................................................................. 11 6-membered rings with 2 or more heteroatoms .................................................................... 11 7-membered rings ................................................................................................................... 13 8-membered rings ................................................................................................................... 13 9-membered rings ................................................................................................................... 14 Uses of heterocyclic compounds .................................................................................................... 14 References ...................................................................................................................................... 14

Heterocyclic compounds heterocyclic compound, also known as a ring structure is basically a co mpound that contains atoms of two distinct elements as members of its ring/rings. Heterocyclic compounds probably constitute the most varied an d the largest number of the family of organic compounds.

Regardless of functionality and structure, every carbocyclic compound ma y be converted into various heterocyclic analogs by just replacing one or more carbon ring atoms with a different element. As a result, heterocycl es have offered a platform for exchange of research in different areas in cluding but not limited to pharmaceutical, medicinal, analytical, and organ ic chemistry of heterocyclic compounds.

The major examples of heterocyclic compounds are most drugs, nucleic acids, majority of synthetic and natural dyes, and majority of biomass su ch as cellulose and related materials. info@apicmo.com

Most Influential Heterocycles In The World Classification Even though heterocyclic compounds may be organic or inorganic compo unds, most have at least one carbon. These compounds can be classifie d according to their electronic structure. Saturated heterocyclic compound s behave in the same way as acyclic derivatives. As a result, tetrahydrof uran and piperidine are conventional ethers and amines with modified st eric profiles.

The study of heterocyclic chemistry therefore focuses mainly on unsatura ted derivatives and applications involve unstrained 5 as well as 6 memb ered rings. This include furan, pyrrole, thiophene, and pyridine. The next large class of heterocyclic compounds is fused to benzene rings, which for furan, pyrrole, thiophene, and pyridine are benzofuran, indole, benzot hiophene, and quinoline, respectively. If two benzene rings are fused, thi s results to another large family of compounds, which are dibenzofuran, carbazole, dibenzothiophene, and aridine. Unsaturated rings may be clas sified based on the participation of a heteroatom in the pi system, conju gated system.

Preparation and reactions

3-membered rings Heterocyclic compounds with 3 atoms in a ring are way more reactive c ourtesy of the ring strain. Heterocycles containing one heteroatom are ge nerally stable. The ones containing two heteroatoms occur, in general as reactive intermediates.

Oxiranes, also known as epoxides are the most common 3-membered h eterocycles. Oxiranes are prepared by reacting peracids with alkenes, wit h good stereospecificity. Oxiranes are more reactive than unsaturated eth ers courtesy of the high angle strain of the 3-membered ring. Addition re actions that proceed by nucleophilic and electrophilic opening of the ring is the most general reaction class.

A reaction of this kind is involved in nitrogen mustards’ pharmacological action that were among the very first anticancer drugs developed. Closur e of intramolecular ring like in the case of anticancer agent mechloretha mine forms an intermediate aziridium ion. The formed biologically active agent attacks proliferating cells including cancer cells through inhibition of their DNA replication. Nitrogen mustards have also been used as antica ncer agents. info@apicmo.com

Most Influential Heterocycles In The World Commercially aziridine, and oxirane are essential bulk industial chemicals.

On large scale production of oxirane, ethylene is directly reacted with o xygen. The chemical reaction, which is the most characteristic of these 3 -membered rings, is that they are susceptible to attack by nucleophilic re agents in order to open the ring as shown below:

The most common three-membered heterocyclic compounds with one hete roatom include: Saturated

Unsaturated

Thiirane (episulfides)

Thiirene

Phosphirane

Phosphirene

Epoxides (oxirane, ethylene oxide)

Oxirene

Aziridine

Azirine

Borirane

Borirene

The most common three-membered heterocyclic compounds with two het eroatoms include Diaziridine as a saturated derivative and Diazirine as a n unsaturated derivative as well as Dioxirane and Oxaziridine.

Four-Membered Rings Various methods of preparation of 4-membered rings heterocycles are sh own in the diagram below. The process of reacting an amine, thiol or 3info@apicmo.com

Most Influential Heterocycles In The World halo with a base is typically effective but with mediocre yields. Dimerizati on and elimination are usual side reactions. Other functions may also co mpete in the reaction.

In the first example, cyclization to an oxirane always compete with forma tion of thietane but the higher nucleophilicity dominates especially if one uses a weak base.

In the second example, formation of both azetidine and aziridine are pos sible but only the latter is seen. Example number four shows that this a pproach to formation of azetidine functions well if there’s no competition.

In the third example, the rigid configuration of the substrate favors forma tion of oxetane and prevents cyclization of oxirane. In examples 5 and 6, the Paterno-Buchi photocyclizations are specially suited to formation of oxetane.

Methods of preparing 4-membered rings heterocycles

Reactions Reactions of 4-membered heterocyclic compounds also demonstrates ring strain influence. The following diagram shows some examples. Acid-catal ysis is a typical feature of various ring-opening reactions shown in exam ples 1,2, and 3a. in reaction 2 of thietane, sulfur undergoes electrophilic chlorination leading to formation of chlorosulfonium intermediate and subs titution of ring-opening chloride ion. In reaction 3b, strong nucleophiles ar e also seen to open the strained ether. Beta-lactones’ cleavage reactions may happen either by acid-catalyzed acyl exchange like seen in 4a. It can also take place by alkyl-O rupture by nucleophiles like in 4b. info@apicmo.com

Most Influential Heterocycles In The World Example number 6 shows an interesting phenomenon of of intramolecula r rearrangement the ortho-ester. Reaction 6 shows Beta-lactam cleavage of penicillin G which shows the enhanced aclylation reaction of the fused ring system.

Examples of reactions of 4-membered heterocyclic compounds

The most useful heterocyclic compounds with 4-membered rings are two series of antibiotics, the cephalosporins and penicillins. The two series c ontain azetidinone ring which is also known as Beta-lactam ring.

Many oxetanes are under investigation as antiviral, anticancer, anti-inflam matory, and antifungal agents. Oxetanones on the other hand are mostly applied in agriculture as bactericides, fungicides, and herbicides and in manufacturing of polymer.

Parent thietane was found in shale oil while its odoriferous derivatives w ork as scent markers for European polecats,ferrets, and minks. Thietanes are applied as fungicides and bactericides in paint, as iron corrosion in hibitors, and in the manufacturing of polymers.

Four-membered rings compounds with a single heteroatom Heteroatom Saturated Unsaturated Heteroatom

Saturated

Unsaturated

Sulfur

Thietane

Azete

Oxygen

Oxetane

Oxete

Nitrogen

Azetidine

Azete

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Most Influential Heterocycles In The World Four-membered rings compounds with two heteroatoms Heteroatom

Saturated

Unsaturated

Sulfur

Dithietane

Dithiete

Oxygen

Dioxetane

Dioxete

Nitrogen

Diazetidine

Diazete

5-membered rings with a single heteroatom Thiophene, furan, and pyrrole are the parent aromatic compounds of 5-m embered rings heterocycles. Here are their structures:

The saturated derivatives of thiophene, furan, and pyrrole are thiophane, tetrahydrofuran, and pyrrolidine respectively. Bicyclic compounds made of thiophene, furan, or pyrrole ring fused to a benzene ring are known as benzothiophene, benzofuran, isoindole (or indole) respectively.

Nitrogen heterocycle pyrrole typically occurs in bone oil that is formed by decomposition of proteins through strong heating. The pyrrole rings are found in the amino acids such as hydroxyproline and proline that are co mponents of various proteins present in high concentrations in structural protein of ligaments, tendons, skin, and bones and collagen.

Pyrrole derivatives are found in the alkaloids. Nicotine is the most comm only known pyrrole that contains alkaloid. Hemoglobin, myoglobin, Vitami n B12, and chlorophylls, are all formed by joining four pyrrole units in a info@apicmo.com

Most Influential Heterocycles In The World large ring system called porphyrin, like that of chlorophyll B demonstrate d below.

Bile pigments are formed through decomposition of porphyrine ring and h ave a chain of 4 pyrrole rings.

Preparation of 5-membered ring heterocycles Industrial preparation of furan proceeds as shown below by the way of a ldehyd, furfural, that is generated from pentose that contains raw materia ls such as corncobs. Similar preparations of thiophene and pyrrole are s hown in the second row of equations.

The third row of equation one demonstrates the general preparation of s ubstituted thiophenes, pyrroles, furans from 1,4-dicarbonyl compounds. M any other reactions leading to formation of substituted heterocycles of thi s type have been started. Two of these procedures have been shown in the second and third reaction. Furan is reduced by palladium-catalyze info@apicmo.com

Most Influential Heterocycles In The World d hydrogenation to tetrahydrofuran. This cyclic ether is a valuable solvent which can not only be converted to 4-haloalkylsulfonates but also 1,4-di halobutanes that can be used to prepare thiolane and pyrrolidine.

Five-membered rings compounds with a single heteroatom Heteroatom

Unsaturated

Saturated

Antimony

Stibole

Stibolane

Arsenic

Arsole

Arsolane

Bismuth

Bismole

Bismolane

Boron

Borole

Borolane

Nitrogen

Pyrrole

Pyrrolidine

Oxygen

Furan

Tetrahydrofuran

5-membered rings with 2 heteroatoms The five-membered ring compounds containing 2 heteroatoms and at lea st one of the heteroatoms is Nitrogen, are known as azoles. Isothiazoles and thiazoles have a nitrogen and sulfur atom in the ring. Compounds with two sulfur atoms are known as Dithiolanes.

Heteroatom

Unsaturated (and partial Saturated ly unsaturated)

Nitrogen

Pyrazole(Pyrazoline)

Pyrazolidine

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Most Influential Heterocycles In The World /nitrogen

Imidazole(Imidazoline)

Imidazolidine

Isoxazole

Isoxazolidine

Oxazoline(oxazole)

oxazolidine

Isothiazole

Isothiazolidine

Thiazoline (Thiazole)

Thiazolidine

Nitrogen/oxygen

Nitrogen/sulfur Oxygen/oxygen

Dioxolane

Sulfur/sulfur

Dithiolane

Some pyrazoles occur naturally. Compounds of this class are prepared b y reacting 1,3-diketones with hydrazines. Most synthetic pyrazole compou nds are used as medicine and dyes. They include fever-reducing analge sic aminopyrine, phenybutazone used in arthritis treatment, the fibre dye and yellow food colour tartrazine, and majority of dyes used in colour ph otography as sensitizing agents.

5-membered rings with 3 heteroatoms There also exist a large group of five-membered ring compounds with at least 3 heteroatoms. One example of such compounds is dithiazoles wh ich contain a nitrogen atom and two sulfur.

6-membered rings with 1 heteroatom The nomenclature used in monocyclic nitrogen-containing 6-membered rin g compounds is here below. Positions on the ring for pyridine are shown, Arabic numerals are more preferred to Greek letters, even though both systems are used. Pyridones are aromatic compounds courtesy of contrib utions to resonance hybrid from charged resonance forms as demonstrat ed for the 4-pyridone.

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Most Influential Heterocycles In The World

Two major coenzymes involved in various crucial metabolic reactions in cells, NAD (also known as coenzyme1) and NADP (also known as coen yme II), are derived from nicotinamide.

The majority of alkaloids contain a piperidine or pyridine ring structure, a mong them piperine (constitutes one of the sharp-tasting contents of blac k and white pepper) and nicotine. Their structures are shown below.

Pyridine which was once extracted from coal tar but is now prepared cat alytically from ammonia and tetrahydrofurfuryl alcohol is a crucial interme diate and solvent used to manufacture other compounds. Vinylpyridines a re crucial monomer building blocks of plastics, and fully saturated piperidi ne, pyridine are used as chemical raw material and rubber processing.

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Most Influential Heterocycles In The World Pharmaceutically useful pyridines Pharmaceutically useful pyridines include the isonicotinic acid hydrazide (t uberculostat isoniazid), the anti-AIDS-virus drug known as nevirapine, nico randil – avasodilator used for controlling angina, phenazopyridine-the urin ary-tract analgesic as well as the anti-inflammatory sulfa drug. Diflufenican, clopyralid, paraquat, and diquat are popular pyridine derivatives which a re used as herbicides.

6-membered rings with 2 or more heteroatoms The 3 monocyclic six-membered ring heterocycles with 2 nitrogen hetero atoms (diazines) are numbered and named as shown below.

Maleic hydrazide is a pyridazine derivative used as a herbicide. Some p yrazines such as aspergillic acid occur naturally. Here are the structures of the aforementioned compounds:

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Most Influential Heterocycles In The World

Pyrazine ring is a component of various polycyclic compounds of industri al and biological importance. Important members of pyrazine family are p henazines, alloxazines, and pteridines. Pharmacologically and biologically, the most crucial diazines are pyrimidines. Cytosine, thymine, and uracil are the 3 of the 5 nucleotide bases which constitute the genetic code in RNA and DNA. Below are their structures:

Vitamin thiamin have a pyrimidine ring and in addition to synthetic barbit urates including amobarbital are commonly used drugs. Morpholine (pare nt tetrahydro-1,4-oxazine) is produced on large scale for use as a fungici de, corrosion inhibitor, and a solvent. Morpholine ring is also found in th e sedative-hypnotic drug trimetozine and some fungicides like fenpropimo rph and tridemorph. Here’s the structural formula for morpholine:

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Most Influential Heterocycles In The World

7-membered rings As the ring size increases, the variety of the compounds that may be ob tained by varying the location, type, and the number of heteroatoms incr eases enormously. However, the chemistry of heterocycles with 7-membe red rings or more is less developed than that of 6 and 5-membered ring heterocyclic compounds.

Oxepine and Azepine rings are crucial constituents of various naturally o ccurring metabolic products of marine organisms and alkaloids. The azep ine derivative known as caprolactam is commercially produced in bulk for use in the manufacture of nylon-6 as an intermediate and in production of synthetic leather, coatings, and films.

7-membered heterocyclic compounds with two or one nitrogen atom in th eir ring are structural units of broadly used psychopharmaceuticals Praze pine (tricyclic antidepressant) and tranquilizer diazepam also known as v alium.

8-membered rings Examples of heterocyclic compounds in this class include azocane, oxoc ane, and thiocane with Nitrogen, oxygen, and sulfur being the respective heteroatoms. Their respective unsaturated derivatives are azocine, oxoci ne, and thiocine respectively.

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Most Influential Heterocycles In The World 9-membered rings Examples of heterocyclic compounds in this class include azonane, oxon ane, and thionane with Nitrogen, oxygen, and sulfur being the respective heteroatoms. Their respective unsaturated derivatives are azonine, oxoni ne, and thionine respectively.

Uses of heterocyclic compounds Heterocycles are useful in several areas of life sciences and technology.

As we have already seen in our discussion, many drugs are heterocycli c compounds.

References IUPAC Gold Book, heterocyclic compounds. Link: W. H. Powell: Revision of the extended Hantzsch-Widman System of No menclature for Heteromonocycles, in: Pure Appl. Chem.1983, 55, 409–41 6; A. Hantzsch, J. H. Weber: Ueber Verbindungen des Thiazols (Pyridins de r Thiophenreihe), in: Ber. Dtsch. Chem. Ges. 1887, 20, 3118–3132 O. Widman: Zur Nomenclatur der Verbindungen, welche Stickstoffkerne e nthalten, in: J. Prakt. Chem. 1888, 38, 185–201;

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