Organic Chemistry 3, Lecture 8, Dr. Yusuf PDF

Org.Chem3 Lec.8 Fused Heterocyclic Compounds Heterocyclic rings systems that are formally derived by fusion with other rings, either carbocyclic or heterocyclic, have a variety of common and systematic names. For example, with the b...

Org.Chem3 Lec.8 Fused Heterocyclic Compounds Heterocyclic rings systems that are formally derived by fusion with other rings, either carbocyclic or heterocyclic, have a variety of common and systematic names. For example, with the benzo-fused unsaturated nitrogen heterocycles, pyrrole provides Indole or isoindole depending on the orientation. Various other important examples of benzofused heterocyclic compounds are Quinoline, Isoquinoline, Benzothiophene, Benzazepine, Dibenzoazepine Carbazole, Acridine, and Benzofuran. Nomenclature For several bicyclic benzo-fused heterocycles, trivial names are permitted, e.g.: 1|Page Org.Chem3 Lec.8 2|Page Org.Chem3 Lec.8 PREPARATION AND REACTIONS OF INDOLE QUINOLINE AND ISOQUINOLINE QUINOLINE Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. Quinoline (benzo[b]pyridine) is a fused heterocyclic system consisting of a benzene ring fused with pyridine cycle.It can be also considered as the heterocyclic analogue of naphthalene (1-azanaphthalene). Systematic IUPAC name: 1-Benzopyridine; Benzo[b]pyridine; Benzo[b]azine; Benzo[b]azabenzene. Other names Quinolin; Chinoline; 1-Azanaphthalene; 1-Benzazine; Benzazine; Benzazabenzene Quinoline is a colourless liquid with an unpleasant odour and boiling point 237 o C. It is miscible with water, ethanol and ether; it may be distilled by steam distillation. Structure of Quinoline: All ring atoms in Quinoline are SP2 hybridize The nitrogen lone pair electrons reside in an SP2 orbital and not involved in the formation of the delocalized π molecular orbital. It shows aromatic properties because its π orbital contains ten electrons & satisfied the Huckel’s rule (n = 2 is 4n+2) 3|Page Org.Chem3 Lec.8 The resonance of Quinoline: Synthesis of Quinoline: 1-(Skraup Synthesis) Mechanism Step I: Glycerol undergoes dehydration with sulfuric acid to give ACROLEIN Step II: Aniline adds to Acrolein (1,4-addition) 4|Page Org.Chem3 Lec.8 Step III: Undergoes ring closure Step IV: Oxidation of 1,2-Dihydroquinoline 2. The Friedlander’s synthesis: Quinoline can also be prepared by the condensation of o- amino Benzaldehyde with acetaldehyde in sodium hydroxide solution. The reaction is shown as follow. 3. The Dobner-Miller Synthesis: This is a modified form of the Skraup synthesis. In this reaction the simple aldehydes and ketones act as precursor of α, β-unsaturated carbonyl compounds. The reaction follows the similar reaction course as in the Skraup synthesis to produce derivatives of quinoline. When acetaldehyde is used as precursor of α, β - unsaturated carbonyl compound 2-methylquinoline is formed. The reaction mechanism is shown as follow. 5|Page Org.Chem3 Lec.8 PHYSICAL PROPERTIES OF QUINOLINE: Quinoline is colourless hygroscopic liquid. It has a characteristic smell similar to that of pyridine. On exposure to air quinoline turns in to yellow coloured. Quinoline is highly aromatic in nature and it has resonance energy 47.3 kcal/mole. Quinoline is a weak base having pKa 4.94. The basicity of quinoline is intermediate between aniline (pKa 4.58) and pyridine (pKa 5.17). CHEMICAL PROPERTIES OF QUINOLINE: The important chemical properties of quinoline are discussed as follow: 1. Basicity: Due to availability of lone pair of electrons on nitrogen, quinoline acts as a base and forms salts with acids and quaternary salts with alkyl halides. a. Reaction with acids: b. Reaction with methyl iodide: 2. Electrophilic substitution: Out of the two fused rings in quinoline, the carbocyclic (benzene) ring is relatively more electron rich and resembles benzene ring while the nitrogen containing ring (less electron rich) resembles with pyridine ring. Therefore the electrophilic substitution in quinoline takes place more readily at benzene ring (at position 5 and 8 of benzene ring) rather than the pyridine ring. The general mechanism of electrophilic substitution on quinoline is shown below. a. At position 5 b. At position 8 6|Page Org.Chem3 Lec.8 i. Bromination: Quinoline undergoes bromination with Br2 in presence of silver sulphate (Ag2SO4) and H2SO4. ii. Nitration: iii. Sulphonation: iv.Oxidation: In presence of KMnO4 quinoline get oxidized to pyridine- 2,3- dicarboxylic acid which on decarboxylation gives nicotinic acid. v. Reduction reactions : The pyrimidine ring is hydrogenated prior to the benzene ring of quinoline. The product of reduction depends much upon the reaction conditions 7|Page Org.Chem3 Lec.8 3. Nucleophilic substitution: Quinoline also gives nucleophilic substitution reactions. Since, pyridine ring of quinoline is comparatively lesser electron rich in comparison to the benzene ring, therefore, nucleophilic substitution in quinoline takes place on pyridine ring. The nucleophilic substitution on pyridine ring takes place at position 2 of pyridine ring. If position 2 is occupied than the substitution takes place at position 4. Reaction of quinoline with strong base sodium amide (sodamide, NaNH2) in liquid ammonia gives 2- aminoquinoline. INDOLE Indole is an aromatic heterocyclic organic compound with formula C8H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five membered nitrogen- containing pyrrole ring. Structure of Indole: The IUPAC name of Indole is 1H-benzo[b] pyrrole. The atoms are numbered as shown in below structure. The numbering begins from the Nitrogen atom and going counter clock wise around the two condensed rings. All the ring atoms in Indole are sp2 hybridized. The sp2 orbitals of all carbon and nitrogen atom overlap with each other and also with the s orbitals of hydrogen to form C-C, C-N, C-H and N-H σ bonds. Each ring atom also possesses a p orbital. These are perpendicular to the plane of the ring. Lateral overlap of these p-orbitals 8|Page Org.Chem3 Lec.8 produce a π molecular orbital containing 10 electrons. Indole is an aromatic compound since it follows the Huckel’s rule (i.e. 4n+2π electron rule) for n=2. Indole is a resonance hybrid of several forms. The different possible forms of Indole are shown in Figure below: preparation of Indole: 1. The Fisher-Indole synthesis: This is the most widely used method for the synthesis of Indole. It involves an acid (Lewis acid) catalysed rearrangement of a phenylhydrazone of an aldehyde or ketone, with the elimination of a molecule of ammonia. Synthesis of 2-methyl indole can be achieved by taking the phenylhydrazone of acetone. The reaction is as shown below: Mechanism: 2. The Madelung Synthesis: This involves the cyclic dehydration of an acyl o-toludine in presence of a strong base and at high temperature. 9|Page Org.Chem3 Lec.8 Mechanism: 3. The Bischler’s synthesis: This method involves the reaction of an aryl amine and α - haloketone or α-haloaldehyde in presence of zinc chloride under thermal or heating condition. The reaction is shown as follow. CHEMICAL PROPERTIES OF INDOLE Electrophilic substitution reactions: Indole is a π -excessive aromatic heterocycles with ten π - electron. Indole gives the electrophilic substitution (the characteristic reactions of aromatic compounds). However, unlike pyrrole, electrophilic substitution in Indole takes place preferentially at C3. 10 | P a g e Org.Chem3 Lec.8 A simple explanation for this can be made by analysis of the intermediates resulting from the attack of an electrophile at C3 and C2 positions. For a reaction at C-3, the energy of activation of the intermediate is lowered because it is possible to delocalize the positive charge through resonance involving the nitrogen lone pair of electrons. 1. Bromination: 2. Nitration: 3. Sulphonation: 4. Friedel crafts alkylation: 11 | P a g e Org.Chem3 Lec.8 5. Diazocoupling or Diazotization reaction: 6. Reimer Tiemann formylation: ISOQUINOLINE : Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline is also obtained by ring fusion of pyridine and with a benzene ring. Synthesis of Isoquinoline In the Bischler-Napieralski reaction a β-phenylethylamine is acylated and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or phosphorus pentoxide. 12 | P a g e Org.Chem3 Lec.8 Chemical properties Isoquinoline reacts with strong mineral acids to form salts. Isoquinoline is a stronger base than quinoline 1. Alkylation and acylation occur on nitrogen 2. Reactions of electrophilic and nucleophilic substitution: Similarly to quinoline electrophilic substitution reactions occur mainly in the 5 or 8 position of isoquinoline. 3. Reduction reactions: Reduction of isoquinoline is more complicated than those for quinoline. 13 | P a g e Org.Chem3 Lec.8 4. Oxidation reactions: Oxidation of isoquinoline with alkaline permanganate solution yields a mixture of phthalic acid and pyridine3,4-dicarboxylic acid 14 | P a g e