six membered heterocyclic compounds with one x

38
ix membered heterocyclic compounds with one ix membered heterocyclic compounds with one N Pyridine A zine re and Properties re and Properties matic sextet is complete without participating of the lone pair of n matic sextet is complete without participating of the lone pair of n Molecular orbital Molecular orbital N ared electrons is in sp2 orbital and in the same plane of the ring ared electrons is in sp2 orbital and in the same plane of the ring l (including N) is ┴ and has one electron, where it overlapped makin l (including N) is ┴ and has one electron, where it overlapped makin system system

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Six membered heterocyclic compounds with one X. Structure and Properties The aromatic sextet is complete without participating of the lone pair of nitrogen. Molecular orbital. The unshared electrons is in sp2 orbital and in the same plane of the ring but other - PowerPoint PPT Presentation

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Page 1: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

N

Pyridine Azine

Structure and PropertiesStructure and Properties

The aromatic sextet is complete without participating of the lone pair of nitrogenThe aromatic sextet is complete without participating of the lone pair of nitrogen

Molecular orbitalMolecular orbital

N

The unshared electrons is in sp2 orbital and in the same plane of the ring but otherThe unshared electrons is in sp2 orbital and in the same plane of the ring but other P orbital (including N) is ┴ and has one electron, where it overlapped making theP orbital (including N) is ┴ and has one electron, where it overlapped making the

aromatic systemaromatic system

Page 2: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

The difference between benzene and pyridineThe difference between benzene and pyridine

11 - -Benzene symmetrical non-polar but pyridine polarBenzene symmetrical non-polar but pyridine polar

N N N N N

It resist electrophilic substitution only in N-atom or at meta-positionIt resist electrophilic substitution only in N-atom or at meta-position

It is highly susceptible to neucleophilic substitutionIt is highly susceptible to neucleophilic substitution

Page 3: Six membered heterocyclic compounds with one X

The difference between benzene and pyridineThe difference between benzene and pyridine

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

22 - -It is basic compound [its basicity less than aliphatic amine]It is basic compound [its basicity less than aliphatic amine]

N:

HCl

CH3 I

N Cl

NCH3 I

Pyridinuim chloride

N-methyl pyridinum Iodide

H

Page 4: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

Like that of benzene ,pyridine is resistant to oxidation, side chain can be oxidizedLike that of benzene ,pyridine is resistant to oxidation, side chain can be oxidized

SimilaritySimilarity

N

CH3

KMnO4

N

COOH

Nicotinic acid pyridine-3- carboxylic acid

Page 5: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

Sources of PyridineSources of Pyridine

Found in coal tarFound in coal tar

N CH3 N N N N CH3

CH3

CH3 CH3 CH3

H3CCH3

2,4,6-collidine2,4-lutidinepicolinepicolinepicolineα β γ

Oxidation of picolines yields the pyridine carboxylic acidsOxidation of picolines yields the pyridine carboxylic acids

N

CH3

KMnO4

N

COOH

Page 6: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

N CH3

KMnO4

N COOH NH

COO

Picolinic acid Zwitter ion

N

KMnO4

N NH

Nicotinic acid Zwitter ion

N

KMnO4

N NH

isonicotinic acid Zwitter ion

CH3 COOH COO

CH3 COOH COO

Page 7: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

The 3- isomer is VitaminThe 3- isomer is Vitamin

The 4- isomer has been used in the form of its hydrazide in treatment of T.BThe 4- isomer has been used in the form of its hydrazide in treatment of T.B

N

CONHNH2

Isonized isonicotinic acid hydrazid

Page 8: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

O

OEtO

+

H H

O

O

OEtO

+

NH3 or NH4OAc

NH

H H

OEtEtO

O O

N

OEtOEt

O O

H3C CH3

FeCl3

H2OCH3H3C

Synthesis of PyridineSynthesis of Pyridine

Hantzsch pyridine synthesisHantzsch pyridine synthesis

Page 9: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one XReaction of PyridineReaction of Pyridine

Pyridine behave as bothPyridine behave as both

Tertiary amine with protonation, alkylation's, acylationTertiary amine with protonation, alkylation's, acylation,, and N-oxidationand N-oxidation

Aromatic compounds with Neocleophilic substitutionAromatic compounds with Neocleophilic substitution and Electrophilic substitutionand Electrophilic substitution

Page 10: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

A: Electrophilic Substitution SA: Electrophilic Substitution SEE

Reaction of PyridineReaction of Pyridine

Pyridine resemble highly deactivated benzene derivativesPyridine resemble highly deactivated benzene derivatives

It undergo nitration , sulfonation, and halogenationIt undergo nitration , sulfonation, and halogenation

only under very vigrous conditiononly under very vigrous condition

chiefly at the 3-positionchiefly at the 3-position N

N

NO2

3- nitropyridine

N

SO3H

3-pyridine sulfonic acid

N

Br

3- bromopyridine

No Reaction

N

Br

3,5-dibromopyridine

Br

+

HNO3, H2SO4

300 C

H2SO4

350 C

Br2

300 C

RX or RCOX

AlCl3

Page 11: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

Why mainly at c-3Why mainly at c-3? ?

N

N N N

H E H E H E

not favoured

N N N

H

EH

E

HE

not favoured

N N N

H

EH

EH

EC-3 attack

C-2 attack

C-4 attack

Page 12: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

In contrast to benzene, Pyridine is very unreactive to SIn contrast to benzene, Pyridine is very unreactive to SEE reaction reaction? ?

11 - -due to electron withdrawing effect of N in the ringdue to electron withdrawing effect of N in the ring

22 - -the intermediate is destabilized by electro negativity effect of Nthe intermediate is destabilized by electro negativity effect of N

N N N N N

33 - -rapid formation of pyridinium cation rapid formation of pyridinium cation ……. So resist further S. So resist further SEE reaction reaction

N

+ E+

N

E

+ve charge in N will not allow any other E+ to enter

Page 13: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

B: Neucleophilic Substitution SB: Neucleophilic Substitution SNN

N

N N N

H Nu H Nu H Nu

specially stable

N N N

H

NuH

Nu

HNu

specially stable

N N N

H

NuH

NuH

NuC-3 attack

C-2 attack

C-4 attack

NNu-

N N NuH

Nuaddition elimination

stabilized by resonance

Page 14: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one XExampleExample

11 - -Chichibabin ReactionChichibabin Reaction

N N N NH2H

NH2- NaH

stabilized intrmediate

Na+

NaNH2

2-aminopyridine

Page 15: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one XExampleExample

22 - -Alkylation or Arylation Reaction by Organolithium compoundsAlkylation or Arylation Reaction by Organolithium compounds

N N N PhH

Ph - NaH

stabilized intermediate

Li+

Ph-Li+

2-phenylpyridine

+ LiH

heatheatN N N OHOH

Cl - Cl-

stabilized intermediate

NaOH

2-hydroxylpyridine

enol

ClNH

O

2-pyridone

keto

N N N

- Br-

stabilized intermediate

Br

BrBr NH2

Br

NH2Br

NH3

Page 16: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

C: Reaction at N-1C: Reaction at N-1

N

NN

CH3I H3C

CH3

CH3

Br

CH3

I

N-methyl pyridinium iodide

H

+

C CH2

H3C

H3C

AlkylationAlkylation

Page 17: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

C: Reaction at N-1C: Reaction at N-1 AcylationAcylation

N

NN

Ph-CO-Cl

CCl

benzoyl chloride

S

SO

OPh Cl

OO

Ph

Cl

O Ph

Page 18: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

C: Reaction at N-1C: Reaction at N-1

Rx with peracidsRx with peracidsRx with lewis acidRx with lewis acid

N

NN

Pyridine -N-Oxide

AlCl3

CH3-COOO-H

CH3COOH + H2

O2

O

AlCl3

Page 19: Six membered heterocyclic compounds with one X

Pyridine N-oxidePyridine N-oxide

N

O

N

O

To activate SE

To activate SN

N

O

N

O

N

O

N

O

N

O

N

O

Page 20: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

N

O

Stabilized intermediate

N

O

HNO3\H2SO4

H NO2

N

ON

NO2

H+

NO2

PCl3

heat+ POCl3

Electrophilic ( Nitration)Electrophilic ( Nitration)

Page 21: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with one XSix membered heterocyclic compounds with one X

Neucleophilic

N

O

Stabilized intermediate

N

O

NaOCH3

H3CO NO2

N

ON

OCH3

-NO2-

OCH3

PCl3

heat+ POCl3

NO2

Page 22: Six membered heterocyclic compounds with one X

D: Oxidation and ReductionD: Oxidation and Reduction

N

NH

NH

1,4-dihydropyridinePipiridine

H2, pt, HCl

25CNa \ E

tOH

ReductionReduction OxidationOxidation

As before oxidation of PicolinesAs before oxidation of Picolines

Page 23: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one X

NN

1

2

3

45

6

7

81

2

3

45

6

7

8

QuinolineQuinolineBenzo[b]pyridineBenzo[b]pyridine

11--azanaphthalineazanaphthaline

IsoquinolineIsoquinolineBenzo[c]pyridineBenzo[c]pyridine

22--azanaphthalineazanaphthaline

Both are weak basesBoth are weak bases Both undergo SE more easly than pyridine in position 5 and 8Both undergo SE more easly than pyridine in position 5 and 8 on benzoid ring, no on the deactivated N-ring Whyon benzoid ring, no on the deactivated N-ring Why??

Like pyridine , N-ring of quinoline and isoquinoline undergo SNLike pyridine , N-ring of quinoline and isoquinoline undergo SN at at αα position position

Page 24: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one X

N

C 5

C 6

C 8

N

N N

N N

E H E H

E

H

E H E H

Page 25: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one X

N

C-2

C-4

N

N N

Nu H Nu H

Nu

H

specially stable

specially stable

N

C-1

C-3

N

N N

specially stable

specially stable

H Nu

Nu

H

Nu

H

Page 26: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one XSynthesis of Quinoline Skraup SynthesisSynthesis of Quinoline Skraup Synthesis

+

CH2OH

CHOH

CH2OH

+

NO2

N

NH2+ C6H5NH2 + H2O

H2SO4

FeSO4

Describe the mechanismDescribe the mechanism

Page 27: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one XBischler Nepieralski SynthesisBischler Nepieralski Synthesis

NH2

CH3COCl

NHC

CH3

OP2O5 heat

N

CH3

Pd \ heatN

CH3

+H2

Page 28: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one X

N

NN

N N

N

N

NO2

NO2SO3H

SO3H

Br

Br

Br2

HNO3

H2SO4\ 0c

H2SO4

300c

NitrationNitration

HalogenationHalogenation

SulfonationSulfonation

Electrophilic SubstitutionElectrophilic Substitution

Page 29: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one XNucleophilic SubstitutionNucleophilic Substitution

N

NN

N

NH

KOH

orNaOH

Bu-Li

OK

O

2-quinoloneBu

Bu

N

NH2

N NH2

1)KN

H2

2)NH

3

AminationAmination

HydroxylationHydroxylationAlkylationAlkylationOr ArylationOr Arylation

with organowith organo--

Page 30: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one XOxidation & ReductionOxidation & Reduction

NNH

NH

NH

H2\pt

LiAlH4

H2\pt

1,2-dihydro quinoline

1,2,3,4-tetrahydro quinoline

cis,trans- decahydro quinoline

ReductionReductionOxidationOxidation

N

N

NH

COOH

COOH

COOH

COOH

O

O

aq KMnO4

alkaline KMnO4

neutralKMnO4

quinolinic acid

phthalic acid

Phthalimide

Page 31: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one X

Other fused ringOther fused ring

N

Acridine

Page 32: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one X DiazinesDiazines

NN

N

N

N

N

pyridazine pyrimidine pyrazine

--Found in folic acidFound in folic acid & & cigarette dercigarette der..

- -Less basic thanLess basic than the other twothe other two

Used only in researchUsed only in research as building block foras building block for more complex compmore complex comp..

Three neucleobasesThree neucleobases found in nucleic acidfound in nucleic acid

cytosinecytosine thyaminethyamine

uraciluracil

Page 33: Six membered heterocyclic compounds with one X

Six membered heterocyclic compounds with two NSix membered heterocyclic compounds with two N DiazinesDiazines

NH

N

NH

NH

NH

NH

NH2

O

O

O

H3C

O

O

Cytosine C

Thyamine T

Uracil U

In DNA & RNA, these bases form H-bonds with their complementary PurinesIn DNA & RNA, these bases form H-bonds with their complementary Purines

DNA A________ TDNA A________ T G________ CG________ C

RNA A________ URNA A________ U G________ CG________ C

Chemical properties of PyrimidinesChemical properties of Pyrimidines

in common with pyridine, as number of N-atoms in the ring increasein common with pyridine, as number of N-atoms in the ring increase the ring the ring ππ- electrons become less energetic- electrons become less energetic

So SSo SEE gets more difficult while S gets more difficult while SNN gets easier gets easier

Page 34: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with two XFused Six membered heterocyclic compounds with two X

PurinesPurines

HN

N NH

NHN

NH

NH

NHN

NH

NH

HN

O

O

O

O

O

O

Hypoxanthine Xanthine uric acid

Contain pyrimidine fused to imidazole ringContain pyrimidine fused to imidazole ring

Page 35: Six membered heterocyclic compounds with one X

Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one X

HN

NH

NH

HN N

N NH

N

N

N NH

N

N

N NH

N

HN

N NH

NN

N NH

N

N

N NH

N

O

O

O

O

Cl

Cl

Cl

NH2

Cl

Cl

NH2I

IH2N

POCl3 aq. NH3

1) NaOH

2) aq. N

H 3,

heat

HI \PH4I

Zn dust

1) HI2) Zn dust

uric acid

guanine

adenine

purine

Page 36: Six membered heterocyclic compounds with one X

MiscellaneousMiscellaneous

NH

S

Phenothiazine

Dibenzothiazine or ThiodiphenylamineDibenzothiazine or Thiodiphenylamine

Drugs containing this nucleus used as antipsychotic and adrenergic blockerDrugs containing this nucleus used as antipsychotic and adrenergic blocker H.W find 2 drugs and draw their structuresH.W find 2 drugs and draw their structures

Page 37: Six membered heterocyclic compounds with one X

MiscellaneousMiscellaneous

N

N

1,4-benzodiazepine

Hypnotic, Sedative, AnxiolyticHypnotic, Sedative, Anxiolytic

Anticonvulsant, Muscle relaxantAnticonvulsant, Muscle relaxant PropertiesProperties

N

N

Cl

OCH3

ValiumValium

Page 38: Six membered heterocyclic compounds with one X

MiscellaneousMiscellaneous

N

N

Cl

OCH3

Cl

NH2

C O+ Cl C

O

CH2Cl

Cl

HN

C O

C

O

CH2

Cl

NH3

N

N

Cl

OH

CH3I

Valium

Preparation of ValiumPreparation of Valium