Heterocyclic compound

1. Prepared By:
Nadim MR Chhipa,
Associate Professor,
ASP & BRI
Mr. Nadim MR Chhipa
1

2. ▪Indole
▪Pyrimidine
▪Purine
Mr. Nadim MR Chhipa 2

3. ▪ 2,3-Benzopyrrole, 1H-Benzo[b]pyrrole
▪ Indole consists of a benzene ring fused to the beta, positions of a pyrrole ring.
▪ It derives its name from the fact that it was first obtained by distilling oxindole, a
degradation product of indigo, with zinc dust.
▪ Indole occurs in coal-tar and in the oils of jasmine and orange blossoms.
▪ It is also found as a part of the total structure of a number of alkaloids and amino
acids e.g, serotonin, reserpine, and tryptophan.
▪ Indole, like pyrrole, produces red colour with a pine splint moistened with
concentrated hydrochloric acid.
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4. ▪ all ring atoms in indole (eight carbons + one nitrogen) are Sp2 hybridized.
▪ Two SP2 orbitals on each atom overlap with each other to form the C-C and C-N o
bonds.The third SP2 orbital on each ring atom overlaps with an S orbital of
hydrogen and forms C-H and N-H a bonds.
▪ •The un hybridized p-orbital of nitrogen is occupied by the nitrogen lone pair of
electrons.
▪ Each carbon atom in ring possess one un hybridized p-orbital
▪ Overlap of these p-orbitals produces delocalized π-molecular orbital containing 10
electrons. (8 electrons from 8 carbons and lone pair of electrons from nitrogen)
▪ Indole shows aromatic properties because the resulting molecular orbital satisfies
the Huckle's rule (4n+2 rule).
▪ The nitrogen lone pair is released into the aromatic system.
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5. ▪ Indole is considered to be hybrid of several canonical forms, some of which are
shown below.
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6. ▪ Properties (Physical)
▪ Indole is a colourless, volatile solid, mp 52oC.
▪ It is sparingly soluble in cold water, but dissolves in hot water and most organic
solvents.
▪ Indole has a powerful odour which is pleasant and flowery in low concentrations.
▪ It is, in fact, used commercially as a perfume base.
▪ In contrast, indole and its 3-methyl derivative (Skalole) are responsible for the
strong offensive odour of faeces.
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7. 1. By the Lipp Synthesis: In this method o-amino-w-chlorostyrene is
heated with sodium ethoxide at l60-170°C,
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8. 2. Fisher Indole Synthesis: Pyruvic acid is first treated with phenyl hydrazine to
form the corresponding phenyl hydrazine.
▪ Then the hydrazine is heated with anhydrous zinc chloride or poly phosphoric acid
to give indole-2-carboxylic acid, which upon decarboxylation yields indole.
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9. 2. Fisher Indole Synthesis:
▪ Acid - catalyzed rearrangement of an arylhydrazone to indole with the elimination
of ammonia
▪ Reaction can be carried out simply by heating together the aldehyde or ketone
and arylhydrazine
▪ Formation of the arylhydrazone and its subsequent rearrangement take place to
give indole, ZnCl2 is used as catalyst.
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10. 2. Fisher Indole Synthesis: Mechanism:
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11. 2. Fisher Indole Synthesis: Mechanism:
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12. 2. Fisher Indole Synthesis:Examples
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13. 3. By she Reissert Synthesis: In this method o-nitrotoluene is condensed with
diethyl oxalate in the presence of a base to form a 2-keto-ester.
This is then reduced with zinc and glacial acetic acid to give indole-2-carboxylic
acid which on decarboxylation gives indole.
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14. 4. From o-Toluidine:This involves treatment of o-toluidine with formic acid to form
N-formyl-o-toluidine.
This undergoes dehydration on heating with potassium t-butoxide to yield indole.
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15. 4. From o-Toluidine:This involves treatment of o-toluidine with formic acid to form
N-formyl-o-toluidine.
This undergoes dehydration on heating with potassium t-butoxide to yield indole.
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16. ▪ 4. Madelung synthesis
▪ Intramolecular cyelization of N-phenylamide using strong base at high temp.
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17. 7.From trans-Indigo This involves oxidation of trans-indigo with potassium
permanganate to form isatin.
Isatin on reduction with zinc and glacial acetic acid first gives dioxindole and finally
oxindole.This is next distilled with zinc dust to give indole.
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18. •Indole is a weak base and also a weak
acid as like pyrrole.
•Indole is a weak base since the lone
pair of electrons of nitrogen atom
contributes to the 4n+2 π electron cloud
(aromatic sextet). Thus, the availability
of these lone pair of electrons is
decreased.
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19. Electrophilic Substitution reactions (C-3 versus C-2):
▪ This is the opposite result to that observed for pyrroles, but can be explained if the
intermediates for each type of reaction are considered.
▪ 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.
▪ This favourable situation is not possible in the corresponding intermediate for attack at
C-2. Any attempt to delocalize the positive charge would now disrupt the pi electrons
system of the benzene ring.
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20. •Electrophilic Substitution reactions (C-3 versus C-2):
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21. •Electrophilic Substitution reactions
▪ Nitration
▪ Common nitrating agents cause acid - catalysed polymerization (high reactivity
of indole).
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22. •Electrophilic Substitution reactions
▪ Nitration
▪ Common nitrating agents cause acid - catalysed polymerization (high reactivity
of indole).
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23. •Electrophilic Substitution reactions
▪ Sulphonation
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24. •Electrophilic Substitution reactions
▪ Halogenation:
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25. •Electrophilic Substitution reactions
▪ Acylation:
▪ acetylation in the presence of sodium acetate, affords N- acetyl indole.
▪ Indole reacts with acetic anhydride, gives 1,3 - diacetylindole predommantly,
which upon HL with aqueous sodium hydroxide at room temperature gives 3 -
acetylindole
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26. •Electrophilic Substitution reactions
▪ Acylation:
▪ Indole may be acetylated with acetyl chloride in the presence of SnCl4 to yield 3-
acetylindole.
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27. •Electrophilic Substitution reactions
▪ Mannich Reaction: reaction with Iminium Ion
▪ Indole undergoes Mannich reaction with formaldehyde and dimethylamine to
give 3-dimethylaminomethylindole (Gramine).
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28. •Electrophilic Substitution reactions
▪ Reimer-Tiemann Formylatlon.
▪ Indole reacts with chloroform in the presence of alkali to yield indole-3-aldehyde
(3-formylindole) and 3-chioroquinoline.
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29. ▪ Oxidation.
▪ Indole may be oxidized by ozone in formamide to give 2-formamido.
benzaldehyde.
▪ Notice that this product is obtained by cleavage of the 2,3-bond in indole.
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30. ▪ Reduction reactions
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31. ▪ Nucleophilic substitution
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32. Mr. Nadim MR Chhipa 32

33. Mr. Nadim MR Chhipa 33

34. Mr. Nadim MR Chhipa 34

35. Mr. Nadim MR Chhipa 35
▪ It is the Diazine, in which nitrogen are present at 1,3 position.
▪ Each atom is sp2 hybridized , planar
▪ the total nu of delocalized e- are 6 (4 of four C, 2 from Ns) follows the
Huckel's rule
▪ Weak Base
▪ The pyrimidine ring system has wide occurrence in nature as
substituted and ring fused compounds and derivatives, including
the nucleotides cytosine, thymine and uracil.