Heterocyclic chemistry

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  • Heterocyclic chemistry: Furan, Thiophene, Pyrrole, Imidazole, Indole

    Dr. Taj Khan Dept. of Pharmaceutical Chemistry, Oriental college of pharmacy Sanpada, New Mumbai.

  • Furan'Drugs:Furosemide, Nitrofurantoin, Nitrofurazone, Prazocin, RanitidineScheele 1780

    67.cdx

  • Less stable than pyrrole & thiopheneless reactive than pyrrole towards E+Aromatic as lone pair of e participate in Pi cloud, follow Huckels rule of aromaticity 4n + 2O and 4 C SP2 hybridised & lie in same plane

  • Synthesis of Furan:1) From carbohydrate:Polysaccharide (Oat)AcidhydrolysisFurfuraldehyde2-furoic acidDecarboxylationFuran

    68.cdx

  • 2) Synthesis of furan from Oxazole

    69.cdx

  • 3) Synthesis of 3-substituted furan from DA adduct

    70.cdx

  • 4) Synthesis of furan by Paal Knorr method: Ring closure mtd. Subst. open chain compd (1,4 diketone) cyclize by acid to give furanMechanism via mono enol formation. Sterically hindered diketone do not cyclize to furan

    71.cdx

  • Chemical reactions of furan:Reaction with acid: F can be hydrolysed easily by acid to give aldehyde. Mild conditions shd be used otherwise protonated F undergoes polymerization can occur.

    F with EWD more stabile to acids

    72.cdx

  • Chemical reactions of furan:Reaction with Base:

    73.cdx

  • Chemical reactions of furan:2) Electrophilic aromatic substitution: more reactive than benzene. 2 position more reactive. Conditions need to be controlled.

    A) Halogenation: proceeds quickly to give mix of either mono and poly subs or resin% of 2 subst product can be increased by using less amt of Cl22- Bromo can be obtd by Br2 in dioxane

    74.cdx

  • Chemical reactions of furan:Electrophilic aromatic substitution:

    B) Nitration: Mild nitrating agents used acetyl nitrate (acetic anhydride + HNO3

    75.cdx

  • Chemical reactions of furan:Electrophilic aromatic substitution:

    C) Sulfonation: Mild sulfonating agents used Pyridine- SO3 complex If H2SO4 used, it gives resin

    76.cdx

  • Chemical reactions of furan:Electrophilic aromatic substitution:

    D) Friedel Crafts reaction: Anhydride and acyl halide need Lewis catalyst. But reactive anhydride like (CF3CO)2O work without catalyst.Alkylation not successful, polymerization. F containing EWD can be alkylated.

    77.cdx

  • Chemical reactions of furan:3) Carbene and nitrene: Cabene add across 2,3 C db.There is not much report of reactions of nitrene with furan

    78.cdx

  • Chemical reactions of furan:4) Reaction with reducing agents: dependent on catalyst, solvent & temp

    79.cdx

  • Chemical reactions of furan:5) Reaction with oxidizing agents: F is O2/air sensitive, 1,4 addition to diene system

    80.cdx

  • Chemical reactions of furan:6) DA Reaction : Furan as a diene reacts with dienophiles to give DA adduct.But due to aromatic character and ring strain in cycloadduct it is thermolabile, revert to SM.

    81.cdx

  • Extra

  • 2 Position reactiveExtra

    82.cdx

  • Extra

  • Thipohene

    Have two pairs of nonbonding e but only 1 pair is in the unhybridized p orbital and is able to overlap with the C of the ring.Mayer 1882Coal tar, pt and animal metabolite

    84.cdx

  • Synthesis of Thiophene:Using Na-Succinate

    Classical mtd Phos. trisulfide ( Red P +S)Industrial mtd use hydrocarbon (butane/butene/1,3-butadiene and elemental S600 0C

    85.cdx

    86.cdx

  • Synthesis of Thiophene:2) Ring closure Mtd A) From unsaturated compds/ Fiesselmann mtd: Condensation Rxn

    87.cdx

  • Synthesis of Thiophene:2) Ring closure MtdB) Paal Knor mtd: General mtd

    88.cdx

  • Synthesis of Thiophene:2) Ring closure Mtd C) Hinsberg Mtd: 1,2 dicarbonyl compound diethylthiodiacetate in presence of st base involved 2 aldol condensation betn reactant and forms half ester

    89.cdx

  • Chemical reactions of thiophene:Reaction with acid: T stable to acid.

    V. st acid can cause polymerization. Orthophosphoric acid under mild condition gives trimer.

    90.cdx

  • Chemical reactions of Thiophen:Reaction with Base:

    91.cdx

  • Chemical reactions of Thiophene:Electrophilic aromatic substitution: more reactive than benzene.

    Pyrrole>furan>Thiophene>Benzene 2 position more reactive. A) Halogenation: Rxn with NBS gives 2- bromo T

    92.cdx

  • Chemical reactions of Thiophene:Electrophilic aromatic substitution: more reactive than benzene.

    Pyrrole>furan>Thiophene>Benzene 2 position more reactive. B) Nitration:

    93.cdx

  • Chemical reactions of furan:Electrophilic aromatic substitution:

    C) Sulfonation: 95% H2SO4 used at rt readily occurs

    94.cdx

  • Chemical reactions of furan:Electrophilic aromatic substitution:

    D) Friedel Crafts reaction: wide variety of choices available

    95.cdx

  • Chemical reactions of furan:3) Reaction with carbene & Nitrene: caboethoxy carbene adds to C2-C3 bond to give cyclopropane compd, which can be opened with acid to give thiophene Beta-acetic esterR=C:RN: acts as E+

    96.cdx

  • Ethyxycarbonylnitrene reacts with T to give 1,4-adduct which loses S to form N-carboethoxypyrrole

    97.cdx

  • Chemical reactions of furan:4) Reaction with Nu: Every positional combination of Nitro and Halo T actiavate system towards SN rxnSeems like normal displacement Rxn

    98.cdx

  • Chemical reactions of furan:5) Reaction with free radicals/ Gomberg Bachmann rxn:1 of the best & simple mtd for synthesis of aryl thiophenes

    99.cdx

  • Chemical reactions of furan:6) Reaction with oxidising agents: Resistant to mild oxidising agents.HNO3 breaks ring to maleic acid and oxalic acid.Peracid (perbenzoic acid attacks S atom)

    Initial sulfoxide ca not be isolated due to dimerization & further oxidation to

    Thiophene 1,1 dioxide/ Thiolane can form its also reactive but isolable

    100.cdx

    101.cdx

  • Chemical reactions of furan:7) Reaction with reducing agents:

    102.cdx

    103.cdx

  • Chemical reactions of furan:8) Diels-Alder reaction: Acetylenic dienophiles. Chelotropic expulsion of S from unstable intermediate, which gives benzene derivative

    104.cdx

  • Pyrrole'Ketorelac, atorvastatinHb, Chlorophyl, Vit B12, bile pigmentRunge 1837Greek: Red

    105.cdx

  • Synthesis methods:1) From Furan

    106.cdx

  • 2)From Primary amine:

    107.cdx

  • The Knorr Synthesis:Imp & widely used mtdCondensation of Alfa amino ketone with another dicarbonyl compound with active methylene grp in presence of acetic acid

    108.cdx

  • Hantzch synthesis of pyrrole:Alfa halo ketone/aldehyde react with beta keto ester (Beta chloro ketone)In presence of N containing base (NH3 or amine) which acts as base as well as solvent.Yield moderate to good.

    109.cdx

  • The Paal Knorr Synthesis of Pyrrole:General mtdCondensation of 1,4 diketone with NH3 or primary amine.

    110.cdx

  • The Piloty Robinsons Synthesis:Monocyclic version of Fischer indole synthesis.Ketazine with st acid to give pyrrole through [3,3] sigmatropic rearrangement of tautomeric divinyl hydrazine

    111.cdx

  • Chemical reactions of Pyrrole:1) Reaction with acid:H attached at N undergoes rapid exchange in acid & alkaliSimilar exchange also possible for H at C under more acidic conditionExchange rate of proton is double than that of protonIsolation of trimer of pyrrole could be achieved by controlled addition of acid

    112.cdx

  • Chemical reactions of Pyrrole:2) Reaction with base:

    pKa 17.5 which is larger than imidazole so pyrrole is wk acid than imidazole.Weaker than phenol but equal to EtOH It reacts with K to liberate H2 and form saltAcidity of P can be increased by putting EWG at position 3 which stabilizes anion by resonance

    113.cdx

  • Resonance structures of furan Thiphene and Pyrrole

  • Mono-C-alkylation of pyrroles cannot be achieved by direct reaction with simple alkyl halides, either alone or with a Lewis-acid catalyst, e.g. pyrrole does not react with methyl iodide even above about 150 C, gives further heating leads to a complex mixture made up mostly of polymeric material together with some poly-methylated pyrroles. The more reactive allyl bromide reacts with pyrrole at room temperature, butmixtures of mono- to tetra-allyl-pyrroles together with oligomers and polymers are obtained.Chemical reactions of Pyrrole:3) Alkylation:

  • Chemical reactions of Pyrrole: 3) Electrophilic Aromatic substitution: e density is more as compared to benzene.ES Rxn occurs similar to benzenoid systemOccurs at 2 position if blocked to other positionMax resonance max stability/probability2 positionFollowed by 3

    114.cdx

  • Chemical reactions of Pyrrole:3) Electrophilic Aromatic substitution:Halogenation: Extremely reactive

    Chlorination (SO2Cl2)Bromination (Br2 CH3COOH)Iodination (I2/KI3)All these gives tetra halo derivativesHard to get mono halo derivativeHalo-pyrroles are v. unstable, decompose in air & light

    115.cdx

  • Chemical reactions of Pyrrole:3) Electrophilic Aromatic substitution:B) Nitration: Extremely reactive

    116.cdx

  • Chemical reactions of Pyrrole:Electrophilic aromatic substitution:

    C) Sulfonation: If H2SO4 used at rt forms polymerSo mild sulfonating agent (Pyridi