Heterocyclic Chemistry Five-membered Heterocycles Pyrrole, Furan and Thiophene.
Six membered heterocyclic compounds with one X Structure and Properties The aromatic sextet is...
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Transcript of Six membered heterocyclic compounds with one X Structure and Properties The aromatic sextet is...
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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
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
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--
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
Fused Six membered heterocyclic compounds with one XFused Six membered heterocyclic compounds with one X
Other fused ringOther fused ring
N
Acridine
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
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
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
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
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
MiscellaneousMiscellaneous
N
N
1,4-benzodiazepine
Hypnotic, Sedative, AnxiolyticHypnotic, Sedative, Anxiolytic
Anticonvulsant, Muscle relaxantAnticonvulsant, Muscle relaxant PropertiesProperties
N
N
Cl
OCH3
ValiumValium
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