HETEROCYCLIC COMPOUNDS 91

CH,OH CH;
CHOH H,sO,
A
CH + 2H,O
H,OH CHO
(b) Michacll addition of aniline to acrolein yields p{phery ylamino) propionaldehyde.
H
OH
CH
2.4.7.2 Quinoline, NH, CH,
Aniline Acroline BPhenylaminopropionaidehyde

Quinoline is abicyclic heterocyclic systemin which benzene ring is fused with a Io) Intramolecular electrophilic substitution on the aromatic ring by protonated aldehyde
ring. Quinolinc was first isolated from coal tar.and was obtainod bythe distillationnof quininc
pyridine followed by del1ydration yields 1, 2-ihydroquinoline.
with alkali. The quinoline nuclcus is prescnt in a number of alkaloids s(quinine and
alkaloid H OH
antimalanals (chloroquine) and analgesics (uricophen). cinchonine), ÇH,
HOH

2.4.7.2,1 Methods of Formation of Quinoline and Its Derivativee H, H-O

Quinoline and its derivatives are preparcd by the following methods: 1. 2-Dihydroquinoline
(6) The Skraup synthesis là) Dehydrogenation of 1,2-dihydroquinoline by nitrobenzene yields quinoline.
This is the commercial method for the preparation of quinoline and many ofits derivatiwe
It consists of heatinga primary aromatic amine, containing at least one vacant ortho positiom + CAH,NO,* 3 - CaH,NH, 2H,0
with an a. B-unsaturated carbonyl compound (or its precursor, generally glycerol) in the
Quinoline
presence ofa condensing agent (concentrated sulphuric acid) and nitrobenzene which a
as amild oxidising agent. Ferrous sulphate is generally added to the reaction mixturet. In Skraup synthesis, acrolein as such is not used since it polymerises under the
make it less violent. reaction conditions. However, it is ageneral method for the preparation ofquinoline
derivatives starting with appropriately substituted anilines.
Quinoline, for example, may be prepared by heating amixture of aniline, glyceral (ii) The Doebner-Miller synthesis
concentrated sulphuric acid, nitrobenzene and ferrous sulphate.
This synthesis is amodification of Skraup's syuthesis. lt involves the condensation ofa
CH,OH primary amine with an aldehyde in the presence of hydrochioric acid which initially forms
Conc. H,SO4, A
CGH,NO,, FeSO4 the a, B- unsaturated aldehyde by self-condensation. Which than reacts with the aromatic
NH, H,OH amine, asillustrated below:
Aniline
Quinoline
a) CçHsNH, + 0= CHCH, CçHN= CHCH,
The mechanism of the reaction involves the following sequence of steps: Ethylidene aniline (An anil)

(a) Dehydration of glycerol to acrolein Nooxidising agent is required because anil formed by the condensation ofaldehyde and 1°
amine acts as the oxidising agent.
92 Organic Chemistry HETEROCYCLIC COMPOUNDS 93

CH;Li
H :CHCI + CH, + LiCI
b) 2CH,CHO CH,Cl,
Aldol condensation CH,CH= CHCHO + H,0 Chloromethylene
Acetaldchyde Crotonaldehyde
CH;Li
+ :CHCIl
H OH -CHA H LiCI
c) ÇH N Quinoline

NH,
CH CH H,0 -H Indole
CH, CH3 CH, 2.4.7.2.2 Physical Properties
Aniline
Crotonaldehyde
Quinoline is a colourless liquid, b.p. 238°C, having an unpleasanttodour and volatile in steam.
/ soluble in water but miscible with ether and alcohol.
sparingly
Itis
Quinoline iis a planar molecule with: aconjugated system of 10 7-electrons and obeys
CoHçNHCH,CH, +
Huckel rule.. The principle resonance forns, contributing to the hybrid, areillustrated below:
N-Ethylaniline CH,
2-Methylquinoline
This method is used, in general, for the synthesis of quinoline homologues. Jete.
(iüi) The Friedelander synthesis
This method involves the alkaline condensation ofo-aminobenzaldehyde
with a carbonyl The resonance energy of the system is 47.3 kcal/mole.
2.4.7.2.3 Chemical Reactions
compound containinga reactive methylene goup(CH ).The mechanism ofthe
reaction involves the initial formation of Schiffbase (T) followed by an internal Oninoline exhibits the reactions of both pyridine and benzene. Some important reactions
aldol-type
condensation between the aryl carbonyl and the activated methylene group. are as follows:

) Basic character
ÇH, HÜ Quinoline contains apair of 2p electrons on nitrogen, Thus, quinoline is atertiary base
CH,
-H,0 and formns quaternary salts on treatment with inorganic acids and reacts with methyl
NH, (U) iodide to yield N-methylquinolinium iodide.
o-Aminobenzaldehyde

HCI

-H,0
HH c Quinoline hydrogenchloride

from water

Quinoline
(iv) Synthesis of quinoline from indole (Ring expansion) O Quinoline methiodide
CHËi
Quinoline may be synthesised from indole by treating it with methyllithium in methylene N-Methylquinoliniumiodide
chloride solution, The mechanism involves the initial fomation of chloromethylene CH,
which slightly mnore basic than aniline.
adds to the indole molecule resulting in the formation of quinoline due to Quinoline is less basic than pyridine but
ring expansion.
 94 Organic Chemistry HETEROCYCLIC COMPOUNDS 95

NH, NaNH,
2-Aminoquinoline
(Chichibabin NH,
reaction)
Alkylation
Pyridine Quaniline Aniline
n-CHoLi 2-Butylquinoline
pKy= 8.7 9.1 9.38
C,Hg-n
DReduction Quinoline
CgH,Li
Electron deficient pyridine ring of quinoline is reduced more easily than benzene 2-Phenylquinoline
The various reduction products formed under different condition are as given belouw. CçHs
) Nucleaphilic substitution of halogens in haloquinolines
Sn/HCI Halogen atoms when present in 2or4-position of quinoline are readily replaced by
H,/Ni nucleophilic reagents as illustrated below.
H,/Pt,

8CH,COOH

Quinoline LiAIHA
1,2, 3, 4-Tetrahydroquinoline

2-Aminoquinoline
NH,
NHJA
-HBr
Br
KCN/A
-KBr
CN
Decahydroquinoline or
Na in lig. NH, w) Electrophilic substitution
1, 2-Dihydroquinoline
Ouinoline undergoes electrophilic substitution reactions like halogenation, nitration,
( ) Oxidation sulphonation and Friedel-Crafts reactions. Since nitrogen atom deactivates the pyridine
(a) Vigorous oxidation with potassium permanganate yields quinolinic ring for electrophilic substitution, the substitution occurs in the benzene ring
acid (pyridine.
2,3-dicartboxylic acid) which decarboxylates to nicotinic acid. preferably at position-S and 8. Br
COOH COOH
Aq. KMnO4 Bromination +
100°C
-Co, Br2, Ag,SO4.
COOH H,SO4
Quinoline Br 5-Bromoquinoline
Pyridine-2, 3-dicarboxylic acid Nicotinic acid
8-Bromoquinoline
(Quinolinic acid)
NO,
(b)Oxidation with peracids or hydrogen peroxide, however, yields
quinoline-N-oxide. Nitration
Conc. HNO,
Conc. H,SO,
or + H,0 NO, S-Nitroquinoline
H,0, Quinoline
8-Nitroquinoline
Quinoline HO,S
Sulphonation 300°C

Quinoline-N-oxide Conc. H,SO4. Rearrangement

() Nucleophilic suhstitution rcactions 200°C
`O,H Quinoline-6
sulphonic acid
(a) Like pyridine, quinoline undergoes nucleophilic substitution reactions at Quinoline-8-sulphonic acid
position-2.
 Organic Chemistry
HETEROCYCLIC COMPOUNDS 97
96

Please note:
3 - b r o m o q u i n o l i n e

and at
bromination
yields 500°C, he
Vapour phase
) pt
2-bromoquinoline.

Vapour phase
Bromination

3-Bromoquinoline
B

-a-e (+ve charge on N)

VI

Aromatic sextet destroycd

VII

lighly unstable
less stable
Br/500°C

Br Atack at position-8
2-Bromoquinoline
activating grOup displays
FriedelÇOCH,
-Crafs:cylationreaction. Foreay
i) Quinoline bearing an

CHCOCI
AICl;
Slow

Ia
- H E
IIl a IV a

Aromatic scxtct is intad Arornatic scxtet of pyridinc ring s inact

more stable stable
OCH; OCH,
8-Methoxyquinoline S-Acetyl-8-Methoxyquinoline
ii) On Nitration with nitric acid and acetic anhydride, quinine gives
Mechanism of electrophilicsubstitution reactions
s3-nitroquinoline
The mechanism ofelectrophilicsubstitution of quinoline atposition-5 and Va VIla
be written as: posiionz VIa

Aromatic sextet destroyed (less stable)

q) Formation of an electrophile
E-Nu E* + :Nu This step is slow and hence is the rate-determining step of the reaction.
Reagent Electrophile Nucleophile
b) Formation of carbocation intermediate (ii) Loss ofa proton to form the product.

Attack at position-5
Fast
Nu: + + H-Nu

Slow
5-Substituted product

Aromatic sextet of pyridine ring

- Nu
Fast
+ H Nu
is intact
more stable Aromatic sextet of pyridine ring is inbxt
stable
la 8-Substituted product
98 Organic Chemistry
Orieniation :
When tack takes place at posiion-6 or posior-7.carbocain fomei z a a
oriy two ooribuingsrcures:lb-Ib)lc-Ic(zegiecting tie u I g
Omatic seaofpytine ring is eTUyed.In conzs atocaionie
takes place apositicn5 or position-8 are stablized by more resonating rutras Ez
lecrophihc stsininains inqinoline akspa nanyapsti-5aipsi
H

HK
E