Heterocyclic Compounds PDF

Dr. O. Erharuyi CHEMISTRY OF HETEROCYCLIC COMPOUNDS Heterocyclic compounds or Heterocycles are cyclic compounds that have one or more of atoms other than carbon, e.g. N, O or S (hetero-atoms), in their rings. Heterocyclic chemistry is the branch of organic chemistry dealing wit...

Dr. O. Erharuyi CHEMISTRY OF HETEROCYCLIC COMPOUNDS Heterocyclic compounds or Heterocycles are cyclic compounds that have one or more of atoms other than carbon, e.g. N, O or S (hetero-atoms), in their rings. Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and applications of these heterocycles. Examples of heterocyclic compounds are pyridine, tetrahydrofuran, thiophene and so on. Among the heterocyclic compounds, there are aromatic, e.g. pyridine, as well as nonaromatic, e.g. tetrahydrofuran, compounds. Similarly, there are saturated (e.g. tetrahydrofuran) and unsaturated (e.g. pyridine) heterocyclic compounds. Heterocycles also differ in their ring sizes, e.g. pyridine has a six-membered ring, whereas tetrahydrofuran is a five-membered oxygencontaining heterocyclic compound. Medicinal importance of heterocyclic compounds More than half of all known organic compounds are heterocyclic compounds. They play important roles in medicine and biological systems. A great majority of important drugs and natural products, e.g. caffeine, nicotine, morphine, penicillins and cephalosporins, are heterocyclic compounds. The purine and pyrimidine bases, two nitrogenous heterocyclic compounds, are structural units of RNA and DNA. Serotonin, a neurotransmitter found in our body, is responsible for various bodily functions. Dr. O. Erharuyi Nomenclature of heterocyclic compounds Most of the heterocycles are known by their trivial names, e.g. pyridine, indole, quinoline, thiophene and so on. However, there are some general rules to be followed in a heterocycle, especially in the use of suffixes to indicate the ring size, saturation or unsaturation as shown in the following table. Dr. O. Erharuyi Monocyclic heterocycles containing three to ten members, and one or more hetero-atoms, are named systematically by using a prefix or prefixes to indicate the nature of the hetero-atoms as presented in the following table. Two or more identical hetero-atoms are indicated by use of the multiplying prefixes di-, tri- or tetra-. When more than one distinct hetero-atom is present, the appropriate prefixes are cited in the name in descending order of group number in the periodic table, e.g. oxa- takes precedence over aza-. If both lie within the same group of the periodic table, then the order is determined by increasing atomic number, e.g. oxa- precedes thia-. In unsaturated heterocycles, if the double bonds can be arranged in more than one way, their positions are defined by indicating the N or C atoms that are not multiply bonded, and consequently carry an ‘extra’ hydrogen atom, by 1H-, 2H- and so on, for example 1H-azepine and 2H-azepine. Important aromatic heterocycles that contain a single hetero-atom include pyridine, quinoline, isoquinoline, pyrrole, thiophene, furan and indole. Dr. O. Erharuyi Derivatives of these heterocyclic compounds are named in the same way as other compounds, by adding the name of the substituent, in most cases as a prefix to the name of the heterocycle, and a number to indicate its position on the ring system, e.g. 2-methylpyridine, 5-methylindole and 3- phenylthiophene. Heterocyclic aromatic compounds can also have two or more hetero-atoms. If one of the hetero- atoms is a nitrogen atom, and the compound has a fivemembered system, their names all end in - azole, and the rest of the name indicates other hetero-atoms. For example, pyrazole and imidazole are two isomeric heterocycles that contain two nitrogen atoms in the ring, thiazole has a sulphur atom and a nitrogen atom in the ring, and oxazole contains an oxygen atom and a nitrogen atom. In imidazole and oxazole, two heteroatoms are separated by a carbon atom, whereas in their isomers, pyrazole and isoxazole, the hetero-atoms are directly linked to each other. The six membered aromatic heterocycles with two nitrogens can exist in three isomeric forms, the most important being pyrimidine. Dr. O. Erharuyi Five-membered unsaturated heterocycles Pyrrole, furan and thiophene: Pyrrole is a nitrogen-containing unsaturated five-membered heterocyclic aromatic compound. It shows aromaticity by delocalization of a lone pair of electrons from nitrogen. A small number of simple pyrroles occur in nature. However, biologically more significant natural pyrroles are tetrameric pyrrole derivatives, known as porphyrins (corrins), which may occur in the free form or as complexes with metallic cations e.g. chlorophyll-a and -b (Mg++), haem (Fe++), cyanocobalamine (Co++). Pyrrole Furan, also known as furane and furfuran, is an oxygen-containing five-membered aromatic heterocyclic compound. It is usually produced when wood, especially pine wood, is distilled. It occurs in furfural which arises from the decomposition of sugars. Ascorbic acid is a naturally occurring dihydrofuran derivative. Furan Dr. O. Erharuyi Thiophene is a sulphur-containing five-membered unsaturated heterocycle. The lone pair electrons of the sulphur are in the 3s orbital, and are less able to interact with the pii electrons of the double bonds. Therefore, thiophene is considered weakly aromatic. Acetylenic thiophene is found in some higher plant species. An important naturally occurring thiophene derivative is biotin (vitamin B7). However, the thiophene ring is present in many important pharmaceutical products. Thiophene Physical properties of pyrrole, furan and thiophene Pyrrole is a weakly basic compound. However, as the nonbonding electrons on the nitrogen atom are part of the aromatic sextet, and no longer available for protonation, it has an extremely low basicity (pKa = ~ 15). Pyrrole accepts a proton on one of the carbon atoms adjacent to the nitrogen atom, whereas the proton on the nitrogen atom can be removed by hydroxide ion to yield its conjugate base. Salts containing the pyrrole anion can easily be prepared by this way. The pair of nonbonding electrons on N in pyrrole is much less available for protonation than the pair on ammonia. Thus, pyrrole is much less basic than NH3 (pKa = 36), i.e. a much stronger acid than NH3. Dr. O. Erharuyi Furan and thiophene are both clear and colourless liquids at room temperature. While furan is extremely volatile and highly flammable with a boiling point close to room temperature (31.4oC), the b.p. of thiophene is 84oC. Thiophene possesses a mildly pleasant odour. Preparation of pyrrole, furan and thiophene A general way of synthesizing heterocyclic compounds is by cyclization of a dicarbonyl or diketo compound using a nucleophilic reagent that introduces the desired hetero-atom. 1. Paal–Knorr synthesis: It is a useful and straightforward method for the synthesis of five-membered heterocyclic compounds, e.g. pyrrole, furan and thiophene. It involves heating of a 1,4-dicarbonyl compound with either ammonia (or a primary amine, hydroxylamines or hydrazines), a dehydrating agent (H2SO4, H3PO4, P2O5, ZnCl2) or an inorganic sulphide (H2S). Dr. O. Erharuyi 2. Hantszch synthesis: A reaction of an α-haloketone with a α-ketoester and NH3 or a primary amine yields substituted pyrrole. Substituted furan can be prepared by using the Feist–Benary synthesis, which is similar to the Hantszch synthesis of the pyrrole ring. In this reaction, α-haloketones react with 1,3-dicarbonyl compounds in the presence of pyridine (as catalyst) to yield substituted furan. Commercial preparation of pyrrole, furan and thiophene - Pyrrole is obtained commercially from fractional distillation of coal tar or by treating furan with NH3 over an alumina catalyst at 400oC. - Furan is synthesized by decarbonylation of furfural (furfuraldehyde), which itself can be prepared by acidic dehydration of the pentose sugars found in oat hulls, corncobs and rice hulls. Dr. O. Erharuyi - Thiophene is found in small amounts in coal tar, and commercially it isprepared from the cyclization of butane or butadiene with sulphur at 600oC. Knorr pyrrole synthesis: this method is generally used for pyrrole synthesis in good yield. It involves the condensation of an α-aminoketone or α-amino-β-ketoester with a ketone containing an activated methylene group or a ketoester in the presence of a base or acid as catalyst. Reactions of pyrrole, furan and thiophene Pyrrole, furan and thiophene possess considerable aromatic character arising from the delocalization of four carbon π-electrons and two lone pair electrons from the hetero-atom. Pyrrole, furan and thiophene therefore undergo electrophilic substitution reactions. Electrophilic substitution generally occurs at C-2, although the C-3 position is attacked when the C-2 position is blocked. Dr. O. Erharuyi The reactivity of this reaction varies significantly among these heterocycles. The ease of electrophilic substitution is usually furan > pyrrole > thiophene > benzene. Clearly, all three heterocycles are more reactive than benzene towards electrophilic substitution. 1. Nitration: Instead of a mixture of nitric acid and sulphuric acid (destroys the heterocycle), nitration of these three heterocycles is carried out with acetyl nitrate (formed from nitric acid and acetic anhydride). Nitration takes place mainly at one of the carbon atoms next to the hetero-atom (2-nitro derivatives). 2. Sulphonation: Pyrrole and furan readily undergo sulphonation with pyridine-sulphur trioxide complex (C5H5N+SO3-) to give the 2-sulphonyl derivative. Thiophene can be sulphonated under stronger acidic condition with 95% sulphuric acid. 3. Friedel-Crafts acylation and alkylation: Thiophene reacts readily with benzoyl chloride in the presence of Lewis acid (AlCl3 or SnCl4) to produce phenyl 2-thienyl ketone. Pyrroles and furans are not stable in the presence of Lewis acids (leads to polymerization), which are necessary for FC alkylations and acylations. Dr. O. Erharuyi 4. Halogenation: Direct halogenation of the unsubstituted five-membered aromatic heterocycles produce a mixture of halo-derivatives, while substituted heterocycles produce a single product. Furan for example is brominated with dioxane dibromide at 0oC to give 2-bromofuran. 5. Formylation (Vilsmeier reaction): Formylation of pyrrole, furan or thiophene is carried out using a combination of phosphorus oxychloride (POCl3) and N, N- dimethylformamide (DMF). This reaction proceeds by formation of the electrophilic Vilsmeier complex, followed by electrophilic substitution of the heterocycle. The formyl group is generated in the hydrolytic workup. Dr. O. Erharuyi 6. Mannich reaction: Pyrrole and alkyl substituted furan undergo the Mannich reaction. Thiophene also undergoes this reaction, but, instead of acetic acid, hydrochloric acid is used. 7. Oxidation: Pyrroles and furans are readily oxidized in air and by oxidizing agents to give degradation products. Thiophene is stable to oxidation, while polysubstituted thiophene can be oxidized by peracids to give sulphones. Dr. O. Erharuyi 8. Reduction: Catalytic hydrogenation of furan witha palladium catalyst gives tetrahydrofuran. 9. Addition reaction of furan: furan readily undergo 1, 4-cycloaddition reaction (diels- Alder reaction). 10. Ring opening of substituted furan: Furan is readily hydrolysed back to a dicarbonyl compound when heated with dilute mineral acid. Dr. O. Erharuyi Six-membered unsaturated heterocycles Pyridine Pyridine (C5H5N) is a nitrogen-containing unsaturated six-membered heterocyclic aromatic compound. A number of molecules possess pyridine or a modified pyridine skeleton in their structures, e.g. nicotinamide, pyridoxine, the antihypertensive drug amlodipine, the antitubercular drug isoniazide. A number of natural alkaloids such as nicotine, anabasine contain the pyridine nucleus. Physical properties of pyridine Pyridine is a liquid (b.p. 115oC) with an unpleasant smell. It is a polaraprotic solvent and is miscible with both water and organic solvents. It is highly aromatic and moderately basic in nature, with a pKa 5.23, i.e. a stronger base than pyrrole but weaker than alkylamines. The lone pair of electrons on the nitrogen atom in pyridine is available for bonding without interfering with its aromaticity. Protonation of pyridine results in a pyridinium ion (pKa = 5.16), which is a stronger acid than a typical ammonium ion, because the acidic hydrogen of a pyridinium ion is attached to an sp2-hybridized nitrogen that is more electronegative than an sp3-hybridizednitrogen. Dr. O. Erharuyi Preparation of pyridine Commercially, pyridine is obtained from distillation of coal tar. 1. Hantzsch synthesis: The reaction of 1,3-dicarbonyl compounds with aldehydes and NH3 provides a 1,4-dihydropyridine, which can be aromatized by oxidation with nitric acid or nitric oxide. Instead of NH3, primary amine can be used to give 1-substituted 1,4- dihydropyridines. 2. Cyclization of 1,5-diketones: The reaction between 1,5-diketones and NH3 produces dihydropyridine systems, which can easily be oxidized to pyridines. 3. Guareschi-Thope synthesis: Condensation of a dicarbonyl compound with ethyl cyanoacetate or cyanoacetate and ammonia in the presence of a base. Dr. O. Erharuyi 4. Condensation of acrolein with ammonia. Reactions of pyridine Pyridine’s electron-withdrawing nitrogen causes the ring carbons to have significantly less electron density than the ring carbons of benzene. The ring carbons are therefore electron deficient especially at the 2 and 4-positions. This makes pyridine less reactive than benzene towards electrophilic aromatic substitution. 1. Nucleophilic aromatic substitutions: Pyridine is more reactive than benzene towards nucleophilic aromatic substitutions because of the presence of electron-withdrawing nitrogen in the ring. Nucleophilic aromatic substitutions of pyridine occur at C-2 (or C-6) and C-4 positions. These nucleophilic substitution reactions are rather facile when better leaving groups, e.g. halide ions, are present. Reaction occurs by addition of the nucleophile to the C=N bond, followed by loss of halide ion from the anion intermediate. Nucleophilic substitution at the C-2 and C-4 positions is also enhanced when the Nitrogen atom is quaternized. Dr. O. Erharuyi 2. Electrophilic substitutions: Pyridine undergoes some electrophilic substitution reactions under drastic conditions, e.g. high temperature, and the yields of these reactions are usually quite low. The main substitution takes place at C-3. 3. Reactions as an amine: Pyridine is a tertiary amine and undergoes reactions characteristic to tertiary amines. It undergoes electrophilic substitution at the ring nitrogen via SN2-like reaction to form quaternary salt. For example, pyridine reacts with mineral acid like HCl, and with alkyl halides to form pyridinium salts. It reacts with peracids or hydrogen peroxide to form an N-oxide. Dr. O. Erharuyi 4. Oxidation: Pyridine ring is generally resistant to oxidizing agents. Substituent alkyl groups can be oxidized without affecting the ring system. 5. Reduction: Treatment of Pyridine with different reducing agents produces dihydropyridine, tetrahydropyridine and piperidine. Dr. O. Erharuyi 6. Ring cleavage: pyridine ring opening occurs under drastic conditions. E.g at high temperature with ozone or catalytic hydrogenation. 7. Dimerization: pyridine dimerizes when treated with raney nickel catalyst or sodium metal in tetrahydrofuran (THF). 2,3-benzo derivatives of five-membered heterocycle The fusing of benzene ring onto the 2,3-position of pyrrole, furan and thiophene produces benzopyrrole (indole), benzofuran and benzothiophene, respectively. Indole Indole contains a benzene ring fused with a pyrrole ring at C-2/C-3 and can be described as benzopyrrole. Indole is a ten pii electron aromatic system achieved from the delocalization of the lone pair of electrons on the nitrogen atom. The indole group of compounds is one of the most prevalent groups of alkaloids found in nature. A number of important pharmacologically active medicinal products and potential drug candidates contain the indole system. Dr. O. Erharuyi For example, the amino acid tryptophan, serotonin (a neurotransmitter), melatonin (a hormone), indole-3-acetic acid (a plant growth hormone) are all substituted indole system. Some naturally occurring indole alkaloids are reserpine, vincristine, vinblastine, strychnine, ergonovine, psilocybin, etc. Physical properties of indole Indole is a weakly basic compound. The conjugate acid of indole is a strong acid (pKa = –2.4). Indole is a white solid (b.p. 253–254oC, m.p. 52–54oC) at room temperature, and possesses an intense faecal smell. However, at low concentrations it has a flowery smell. Indole is slightly soluble in water, but readily soluble in organic solvents, e.g. ethanol, ether and benzene. Preparation of indole Fischer indole synthesis: Cyclization of arylhydrazones by heating with an acid or Lewis acid catalyst yields an indole system. The most commonly used catalyst is ZnCl2. The disadvantage of this reaction is that unsymmetrical ketones give mixtures of indoles if R’ also has an α- methylene group. Leimgruber synthesis: Aminomethylenation of nitrotoluene followed by hydrogenation yield indole. Madelung indole synthesis: vigorous base treatment of autho toluidine at high temperature. Dr. O. Erharuyi Reactions of indole Electrophilic aromatic substitution Electrophilic aromatic substitution of indole occurs on the five-membered pyrrole ring, because it is more reactive towards such reaction than a benzene ring. As an electron-rich heterocycle, indole undergoes electrophilic aromatic substitution primarily at C-3, for example bromination of indole. The Mannich reaction is another example of electrophilic aromatic substitution where indole can produce an aminomethyl derivative. Similarly, using the Vilsmeier reaction an aldehyde group can be brought in at C-3 of indole. Reduction: reduction with a variety of reducing agents e.g. tin in HCl, sodium borohydride, H2/Pd, etc gives indoline, further reduction can give octahydroindole. Diazocoupling: indole couple with phenyl diazonium salt to give 3-phenylazo derivative. Dimerization: upon treatment with HCl gas in benzene, indole dimer is formed. Dr. O. Erharuyi 2,3-benzo derivatives of six-membered heterocycle The fusing of benzene ring onto the 2,3-position of pyridine, pyran and thiopyran produces benzopyridine (Quinoline), benzopyran (Chromene) and benzothiopyran (Thiochromene), respectively. Quinoline and isoquinoline Quinoline and isoquinoline, known as benzopyridines, are two isomeric heterocyclic compounds that have two rings, a benzene and a pyridine ring, fused together. In quinoline this fusion is at C2/C3, whereas in isoquinolinethis is at C3/C4 of the pyridine ring. Like benzene and pyridine, these benzopyridines are also aromatic in nature. A number of naturally occurring pharmacologically active alkaloids possess quinoline and isoquinoline skeleton. For examples, papaverine from Papaver somniferum, morphine from opium poppy, emetine are isoquinoline alkaloid. Quinine from Cinchona barks is a quinoline alkaloid that has antimalarial properties. Preparation of quinoline and isoquinoline Quinoline synthesis Skraup synthesis: This is used to synthesize the quinoline skeleton by heating aniline with glycerol, using sulphuric acid as a catalyst and dehydrating agent. Ferrous sulphate is often added as a moderator, as the reaction can be violently exothermic. The most likely mechanism of Dr. O. Erharuyi this synthesis is that glycerol is dehydrated to acrolein, which undergoes conjugate addition to the aniline. This intermediate is then cyclized, oxidized and dehydrated to give the quinoline system. Isoquinoline synthesis Pictet–Spengler synthesis: This involves the reaction of β-phenylethylamine with an aldehyde to produce an imine, which undergoes acid-catalysed cyclization, resulting in the synthesis of the tetrahydroisoquinoline system. The tetrahydroisoquinoline is aromatized by palladium dehydrogenation to produce an isoquinoline system. Reactions of quinoline and isoquinoline Electrophilic aromatic substitutions: Quinoline and isoquinoline undergo electrophilic aromatic substitution on the benzene ring, because a benzene ring is more reactive than a pyridine ring towards such reaction. Substitutiongenerally occurs at C-5 and C-8, e.g. bromination of quinoline and isoquinoline. Dr. O. Erharuyi Nucleophilic substitutions: Nucleophilic substitutions in quinoline and isoquinoline occur on the pyridine ring because a pyridine ring is more reactive than a benzene ring towards such reaction. While this substitution takes place at C-2 and C-4 in quinoline, isoquinoline undergoes nucleophilic substitution only at C-1.