User:Benjah-bmm27/degree/3/KIBM

Heterocycles, KIBM

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Azoles

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Reactivity

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  • 1,3-azoles tend to undergo clean electrophilic substitution at C5, but are less reactive than pyrrole
  • 1,2-azoles generally undergo electrophilic substitution at C4

Synthesis

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Anion chemistry

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Indoles

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Reactions of indoles

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Indole syntheses

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Carbazoles

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Benzofurans

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Reactions of benzofurans

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  • Benzofurans differ from indoles in that they tend to undergo electrophilic substitution in the 2 position, rather than the 3 position
    • This is probably because furan is far less aromatic than pyrrole, so the benzene ring of a benzofuran has more influence on the substitution pattern
  • Vilsmeier reaction, nitration and lithiation at occur at the 2 position
  • With bromine, benzofurans undergo electrophilic addition across the furan double bond - suggesting less aromaticity than indole

Benzofuran syntheses

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  • O-Aryl hydroxylamines react with ketones to give O-aryl ketoximes, which cyclize and dehydrate in acid to benzofurans, by a mechanism analogous to that of the Fischer indole synthesis
  • Sodium phenoxides react with α-bromoketones to give α-phenoxyketones, which cyclize and dehydrate in acid to benzofurans. This is the oxygen equivalent of the Bischler indole synthesis.

Quinolines and isoquinolines

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  • Quinoline
  • Isoquinoline
  • Both π deficient heterocycles
  • Their physical properties and chemical reactivity are very similar, but their syntheses are very different

Reactions of quinolines and isoquinolines

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Electrophilic aromatic substitution

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  • Quinoline undergoes nitration and bromination in the 5 and 8 positions (1:1 mixture of isomers)
  • Isoquinoline is more selective and only the 5 position is substituted

Nucleophilic substitution

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Anion chemistry

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  • 2-alkylquinolines have an acidic proton that can be removed by BuLi, forming an aza enolate that reacts with electrophiles

Reduction

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  • There are a number of important dihydroquinoline and tetrahydroquinoline drugs, so reduction of quinolines is industrially important
  • Lithium aluminium hydride reduces quinolines to dihydroquinolines, formally adding H2 across the N=C2 double bond
  • H2/Pt reduces the pyridine ring, leaving the benzene ring intact, thereby forming the tetrahydroquinoline
  • H2/Pd in concentrated hydrochloric acid reduces only the benzene ring, leaving the pyridine ring untouched
    • HCl must protonate the nitrogen sp2 lone pair, somehow deactivating the pyridine ring to hydrogenation.

Quinoline syntheses

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Isoquinoline syntheses

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Others

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Quiz

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