heterocyclic - faculty.psau.edu.sa · 4-to understand methods of reaction ... it resist...

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Heterocyclic

Chemistry

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1-To know types of six member heterocyclic ring

2- To Know Sources of six member of Heterocyclic

compounds

3- To Know syntheses of six member of

Heterocyclic compounds

4-To understand methods of reaction six member of

Heterocyclic compounds

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Six Membered

Aromatic

Heterocycles

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

P orbital (including N) is ┴ and has one

electron, where it overlapped making

the aromatic system

Six membered heterocyclic compounds (one N )

Pyridine

important solvent

& base (~ 3o amine)

Reactions:

1) Electrophilic

substitution in

pyridine

EAS (much less

reactive than

benzene ~ nitro)

N

KNO3, H2SO4, 370o

N

NO2

3% yield

H2SO4, SO3, HgSO4

220o, 24 hours

N

SO3

H

Br2, 300o

N N

Br Br Br

+

Friedel-Craftsno reaction


N

N

N

H Y

Y

H

Y

HN

Y

HN

Y

H

N

Y

H

N

Y

H

N

H Y

N

H Y

Deactivated to EAS due to electronegativity of NitrogenDirects beta due to destabilization of alpha and gamma

Six membered heterocyclic compounds (one N)

Comparison between benzene and pyridine

1- Benzene symmetrical non-polar but pyridine polar

N N NN N

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

It is highly susceptible to neucleophilic substitution

Pyridine is less active, than benzene toward electrophilic agents, because nitrogen is more

electronegative, than carbon and acts like an electron withdrawing substituent, including the

meta-directing effect.


N CH3H3C

HNO3

H2SO4 N CH3H3C

NO2

81%

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

N:

HCl

CH3 I

N Cl

NCH3 I

Pyridinuim chloride

N-methyl pyridinum Iodide



Like that of benzene, pyridine is resistant to oxidation, side

chain can be oxidized

Similarity

N

CH3

KMnO4

N

COOH

Nicotinic acid 3-pyridine carboxylic acid



CH3KMnO4

Toluene

COOH

Benzoic acid

CH2CH3KMnO4

COOH

Benzoic acid

+ + OH2CO2

It Found in coal tar

N CH3 N N N N CH3

CH3

CH3 CH3 CH3

H3CCH3

2,4,6-collidine2,4-lutidinepicolinepicolinepicoline

α β γ

Oxidation of picolines yields the pyridine carboxylic acids

N

CH3

KMnO4

N

COOH


Sources of Pyridine

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


α

The 3- isomer is Vitamin

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

N

CONHNH2

Isoniazid isonicotinic acid hydrazid


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

Hantzsch pyridine synthesis


Synthesis of Pyridine

The Hantzsch pyridine synthesis typically uses a 2:1:1 mixture of a β-keto acid (often

acetoacetate), an aldehyde (often formaldehyde), and ammonia or its salt as the

nitrogen donor. First, a double hydrogenated pyridine is obtained, which is then

oxidized to the corresponding pyridine derivative.

Reaction of Pyridine

B) Aromatic compounds with

Neocleophilic substitution

and Electrophilic substitution


Pyridine behave as both

A) Electrophilic substitution

Tertiary amine with protonation,

alkylation's, acylation,

and N-oxidation

A: Electrophilic Substitution SE

Reaction types of Pyridine

Pyridine resemble

highly deactivated

benzene derivatives

It undergo nitration ,

sulfonation, and

halogenation

only under very

vigorous condition

chiefly 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


Why mainly at c-3 ?

N

N N N

H E H E H E

not favoured

NN N

H

EH

E

H

E

not favoured

N N N

H

E

H

E

H

EC-3 attack

C-2 attack

C-4 attack

Six membered heterocyclic compounds (pyridine )

mainly at c-3



elec. (+ ve) par

In contrast to benzene, Pyridine is very unreactive to SE reaction ?

1- due to electron withdrawing effect of N in the ring

2- the intermediate is destabilized by electro negativity effect of N

N N NN N

3- rapid formation of pyridinium cation …. So resist further SE reaction

N

+ E+

N

E

+ve charge in N will not allow

any other E+ to enter




B: Neucleophilic Substitution SN

N

N N N

H Nu HNu H Nu

specially stable

NN N

H

Nu

H

Nu

H

Nu

specially stable

N N N

H

Nu

H

Nu

H

Nu

C-3 attack

C-2 attack

C-4 attack



Nu. (- ve)

Ortho or

para

Example

1- Chichibabin Reaction

N N N NH2H

NH2- NaH

stabilized intrmediate

Na+

NaNH2

2-aminopyridine



Example

2- Alkylation or Arylation Reaction by Organolithium compounds

N N N PhH

Ph - NaH

stabilized intermediate

Li+

Ph-Li+

2-phenylpyridine

+ LiH

heatheat

N N N OHOH

Cl - Cl-


NaOH

2-hydroxylpyridine

enol

ClNH

O

2-pyridone

keto

N N N

- Br-


Br

Br

Br NH2

Br

NH2

Br

NH3



C: Reaction at N-1

N

NN

CH3I H3C

CH3

CH3

Br

CH3

I

N-methyl pyridinium iodide

H

+

C CH2

H3C

H3C

Br-

Alkylation

Six membered heterocyclic compounds (one N)


electrophilic

C: Reaction at N-1

Acylation

N

NN

Ph-CO-Cl

C

Cl

benzoyl chloride

S

SO

O

Ph Cl

OO

Ph

Cl

O Ph



C: Reaction at N-1

Rx with peracidsRx with lewis acid

N

NN

Pyridine -N-Oxide

AlCl3

CH3-COOO-H

CH3COOH + H2

O2

O

AlCl3



Pyridine N-oxide

N

O

N

O

To activate SE

To activate SN

N

O

N

O

N

O

N

O

N

O

N

O



N

O

Stabilized intermediate

N

O

HNO3\H2SO4

H NO2

N

O

N

NO2

H+

NO2

PCl3

heat+ POCl3

Electrophilic ( Nitration)



Six membered heterocyclic compounds with one X

Neucleophilic

N

O

Stabilized intermediate

N

O

NaOCH3

H3CO NO2

N

O

N

OCH3

-NO2-

OCH3

PCl3

heat

+ POCl3

NO2


D: Oxidation and Reduction

N

NH

NH

1,4-dihydropyridinePipiridine

H2, pt, H

Cl

25CNa

\ EtO

H

Reduction

Oxidation As before oxidation of Picolines



Six membered heterocyclic compounds with tow N

Diazines

N

N

N

N

N

N

pyridazinepyrimidine pyrazine

-Found in folic acid

& cigarette derivative.

- Less basic than

the other two

Used only in research

as building block for

more complex comp.

Three neucleobases

found in nucleic acid

cytosine, thyamine, uracil

NH

N

NH

NH

NH

NH

NH2

O

O

O

H3C

O

O

Cytosine C

Thyamine T

Uracil U

DNA A________ T

G________ C

RNA A________ U

G________ C

Chemical properties of Pyrimidines

in common with pyridine, as number of N-atoms in the ring increase

the ring π- electrons become less energetic

So SE gets more difficult while SN gets easier

Six membered heterocyclic compounds with tow N

Diazines

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

NN

1

2

3

45

6

7

81

2

3

45

6

7

8

Quinoline

Benzo[b]pyridine

1-azanaphthaline

Isoquinoline

Benzo[c]pyridine

2-azanaphthaline

Both are weak bases

Both undergo SE more easly than pyridine in position 5 and 8

on benzoid ring, no on the deactivated N-ring Why?

Like pyridine , N-ring of quinoline and isoquinoline undergo SN

at α position


N

Acridine

Fused ring

N

C 5

C 6

C 8

N

N

N

N N

EH E

H

E

H

E H

EH


Quinoline

N

C-2

C-4

N

N N

Nu H Nu H

Nu

H

specially stable

specially stable

N1

2

3

45

6

7

8

N

C-1

C-3

N

N N

specially stable

specially stable

H Nu

Nu

H

Nu

H


Isoquinoline

N

1

2

3

45

6

7

8

Skraup Synthesis+

CH2OH

CHOH

CH2OH

+

NO2

N

NH2+ C6H5NH2 + H2O

H2SO4

FeSO4


Synthesis of Quinoline

1- Dehydration of glycerol by hot H2SO4CH2

HC

HC

OH

OH

H

H

O

CH2

CH

HC O

Acrolein

+ 2 H2OH2SO4 / heat

2- Nuecleophlic addition

C

NH2

O

HCH

CH2

NH

CH2

CH2

HC

O

+ H+

- H+

NH

CH2

CH2

HC

O

+ H+

NH

CH2

CH2

HC

OH

Dehydration

NH

+ H2O


Synthesis of Quinoline (Skraup Synthesis)

3- Elecetrophlic attack on aromatic ring by electron deficient Carbonyl carbon of

protonated aldehyde

4- Oxidation by nitrobenzene

NH

3 + C6H5NO2

N

+ C6H5NH2 + 2 H2O

H+


(Bischler Nepieralski Synthesis)

NH2

CH3COCl

NHC

CH3

OP2O5

heat

N

CH3

Pd \ heatN

CH3

+H2

Synthesis of Quinoline

N

NN

N N

N

N

NO2

NO2

major

minor

SO3H

SO3H

Br

Br

Br2

HNO 3

H 2SO 4

\ 0c

H 2SO 4

300c

majorminor

1 : 1

Nitration

Halogenation

Sulfonation

Electrophilic Substitution


Reaction of Quinoline

Nucleophilic Substitution

N

NN

N

NH

KOH

orNaOH

Bu-Li

major minor

OK

O

2-quinolone

Bu

Bu

N

NH2

N NH2

majorminor

1)KN

H2

2)NH

3

Amination

Hydroxylation

Alkylation

Or Arylation

with organo-



Oxidation & Reduction

NNH

NH

NH

H2\pt

LiAlH4

H2\pt

1,2-dihydro quinoline

1,2,3,4-tetrahydro quinoline

cis,trans- decahydro quinoline

Reduction

Oxidation

N

N

NH

COOH

COOH

COOH

COOH

O

O

aq KMnO4

alkaline KMnO

4

neutral

KMnO4

quinolinic acid

phthalic acid

Phthalimide



Fused Six membered heterocyclic compounds with more

Than one N

Purines

HN

NNH

NHN

NH

NH

NHN

NH

NH

HN

O

O

O

O

O

O

Hypoxanthine Xanthine uric acid

Contain pyrimidine fused to imidazole ring

HN

NH

NH

HN N

N NH

N

N

N NH

N

N

N NH

N

HN

N NH

NN

N NH

N

N

NNH

N

O

O

O

O

Cl

Cl

Cl

NH2

Cl

Cl

NH2I

IH2N

POCl3 aq. NH3

1) NaO

H

2) aq. N

H 3,

heat

HI \PH4I

Zn dust

1) HI2) Zn dust

uric acid

guanine

adinine

purine

Fused Six membered heterocyclic compounds with more

Than one N

Miscellaneous

NH

S

Phenothiazine

Dibenzothiazine or Thiodiphenylamine

Drugs containing this nucleus used as antipsychotic and

adrenergic blocker

Fused Six membered heterocyclic compounds

N

N

1,4-benzodiazepine

Hypnotic, Sedative, Anxiolytic

Anticonvulsant, Muscle relaxant

Properties

N

N

Cl

O

CH3

Valium

H.W find 2 drugs and draw their structures

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 Valium

Fused Six membered heterocyclic compounds

Miscellaneous

heterocyclic - faculty.psau.edu.sa · 4-to understand methods of reaction ... it resist...

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