The document provides information about quinoline, isoquinoline, and indole. It discusses their structures, properties, synthesis methods, and reactions. Quinoline and isoquinoline are both heterocyclic aromatic compounds composed of a benzene ring fused to a pyridine ring. They undergo similar electrophilic and nucleophilic substitution reactions. Common synthesis routes for quinoline include the Skraup, Doebner-Miller, and Conrad-Limpach reactions. Isoquinoline synthesis methods include the Pomeranz-Fritsch and Bischler-Napieralski reactions. Indole is a bicyclic molecule with a benzene and pyrrole ring. It does not readily
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FUSED HETEROCYCLES WITH ONE HETEROATOM
1. FUSED HETEROCYCLES
WITH ONE HETEROATOMS
BY â VISHAL SINGH SOLANKI
A.P. AT IDEAL INSTITUTE, POSHERI, WADA, PALGHAR, M.H.
EMAIL â vishalsolanki393@gmail.com
4. Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N.
It is a colourless hygroscopic liquid with a strong odour.
Aged samples, especially if exposed to light, become yellow and later brown.
Quinoline is only slightly soluble in cold water but dissolves readily in hot water and most
organic solvents.
Quinoline itself has few applications, but many of its derivatives are useful in diverse
applications.
A prominent example is quinine, an alkaloid found in plants.
Over 200 biologically active quinoline and quinazoline alkaloids are identified.
4-Hydroxy-2-alkylquinolines (HAQs) are involved in antibiotic resistance.
INTRODUCTION
5. Quinoline, any of a class of organic compounds of the aromatic heterocyclic
series characterized by a double-ring structure composed of a benzene and
a pyridine ring fused at two adjacent carbon atoms.
The benzene ring contains six carbon atoms, while the pyridine ring contains
five carbon atoms and a nitrogen atom.
The simplest member of the quinoline family is quinoline itself,
a compound with molecular structure C9H7N.
CONTIâŚ
7. All ring atoms in Quinoline are SP2 hybridize.
The nitrogen lone pair electrons reside in an SP2 orbital and not involved in the
formation of the delocalized Ď molecular orbital.
It shows aromatic properties because its Ď orbital contains ten electrons & satisfied the
Huckelâs rule (n = 2 is 4n+2).
RESONANCE
8. PHYSIAL PROPERTIES
Chemical formula C9H7N
Molar mass 129.16 g/mol
Appearance Colorless oily liquid
Density 1.093 g/mL
Melting point â15 °C (5 °F; 258 K)
Boiling point 237 °C (459 °F; 510 K) , 760 mm Hg; 108â110 °C
(226â230 °F), 11 mm Hg
Solubility in water Slightly soluble
Solubility Soluble in alcohol, ether, and carbon disulfide
Other IUPAC name 1-Benzopyridine, Benzo[b]pyridine
9. 1. Combes quinoline synthesis using anilines and β-diketones.
2. Conrad-Limpach synthesis using anilines and β-keto esters.
3. Doebner reaction using anilines with an aldehyde and pyruvic acid to form quinoline-
4-carboxylic acids
4. Doebner-Miller reaction using anilines and ι,β-unsaturated carbonyl compounds.
5. Gould-Jacobs reaction starting from an aniline and ethyl ethoxy methylene malonate
6. Skraup synthesis using ferrous sulfate, glycerol, aniline, nitrobenzene, and sulfuric
acid.
7. Friedländer synthesis using 2-aminobenzaldehyde and acetaldehyde
SYNTHESIS
11. In the archetypal Skraup reaction, aniline is heated with sulfuric acid, glycerol,
and an oxidizing agent such as nitrobenzene to yield quinoline.
SKRAUP SYNTHESIS
13. The DoebnerâMiller reaction is the organic reaction of an aniline with Îą,β-unsaturated
carbonyl compounds to form quinolines.
The reaction is catalyzed by Lewis acids such as tin tetrachloride and scandium(III)
triflate and Brønsted acids such as p-toluenesulfonic acid, perchloric acid, amberlite and iodine.
DOEBNERâMILLER SYNTHESIS
14. CONRADâLIMPACH SYNTHESIS
The ConradâLimpach synthesis is the condensation of anilines (1) with β-ketoesters (2) to
form 4-hydroxyquinolines (4) via a Schiff base (3). The overall reaction type is a combination of
both an addition reaction as well as a rearrangement reaction.
16. The Friedländer synthesis is a chemical reaction of 2-amino
benzaldehydes with ketones to form quinoline derivatives.
This reaction has been catalysed by trifluoroacetic acid, toluene sulfonic
acid, iodine, and Lewis acids.
FRIEDLĂNDER SYNTHESIS
17. In the first mechanism 2-amino substituted carbonyl compound 1 and carbonyl
compound 2 react in a rate-limiting step to aldol adduct 3.
This intermediate loses water in an elimination reaction to unsaturated carbonyl
compound 4 and then loses water again in imine formation to quinoline 7.
In the second mechanism the first step is Schiff base formation to 5 followed by
Aldol reaction to 6 and elimination to 7.
MECHANISM
20. Electrophilic substitution reactions occur on the ring C-atoms, mainly on those of the more activated benzene
moiety.
Electrophilic substitution reactions occur in positions 5 and 8 of quinoline.
Nucleophilic substitution proceeds faster in quinoline than in pyridine.
Nucleophilic substitution of quinoline occurs in the electron deficient pyridine ring, as a rule in the position 2
or 4.
Treatment of quinoline with nitrating mixture results in 5and 8-nitroquinolines.
Sulphonation of quinoline produces different products depending on the reaction temperature.
At 220°C quinoline8sulphonic acid is formed predominantly͞ At 300°C, quinoline6sulphonic acid is the sole
product.
When heating to 300°C quinoline8sulphonic acid is converted into quinoline6sulphonic, which is the
thermodynamically favoured Sulphonation product.
ELECTROPHILIC AND NUCLEOPHILIC SUBSTITUTION
REACTIONS
21. The pyridine ring is hydrogenated prior to the benzene ring of quinoline.
The product of reduction depends much upon the reaction conditions.
The alkaline permanganate solution causes oxidative cleavage of the benzene ring in
quinoline to give quinolinic acid (pyridine 2,3-dicarboxylic acid). The reaction of
quinoline with per-oxy carboxylic acids leads to its N-oxide.
Heteroatom reactions: The nitrogen in Quinoline, which undergoes protonation,
alkylation, acylation, etc. Quinoline is a weaker base than pyridine.
OXIDATION AND REDUCTION REACTIONS.
23. APPLICATION
1. Quinoline is used in the manufacture of dyes, the preparation of hydroxyquinoline sulphate and niacin.
2. It is also used as a solvent for resins and terpenes.
3. Quinoline is mainly used as in the production of other specialty chemicals.
4. Its principal use is as a precursor to 8-hydroxyquinoline, which is a versatile chelating agent and
precursor to pesticides.
5. Its 2- and 4-methyl derivatives are precursors to cyanine dyes. Oxidation of quinoline affords quinolinic
acid (pyridine-2,3-dicarboxylic acid), a precursor to the herbicide sold under the name "Assert".
6. The reduction of quinoline with sodium borohydride in the presence of acetic acid is known to
produce Kairoline A.
7. Quinoline has several anti-malarial derivatives, including quinine, chloroquine, amodiaquine,
and primaquine.
8. Quinolines are reduced to tetrahydroquinolines enantio-selectively using several catalyst systems.
26. Iso-quinoline is a heterocyclic aromatic organic compound.
It is a structural isomer of quinoline.
Iso-quinoline and quinoline are benzo-pyridines, which are composed of a benzene ring
fused to a pyridine ring.
In a broader sense, the term iso-quinoline is used to make reference to iso-
quinoline derivatives.
1-Benzylisoquinoline is the structural backbone in naturally
occurring alkaloids including papaverine.
The iso-quinoline ring in these natural compound derives from the aromatic amino
acid tyrosine.
INTRODUCTION
27. Iso-quinoline is a colourless hygroscopic liquid at room temperature.
It crystallizes platelets that have a low solubility in water but dissolve well in ethanol,
acetone, diethyl ether, carbon di-sulfide, and other common organic solvents. It is also
soluble in dilute acids as the protonated derivative.
Iso-quinoline is a crystalline substance with a quinoline like odourÍž Its melting point is
24.6°C.
CONTIâŚ
29. Chemical formula C9H7N
Molar mass 129.162 g¡mol
â1
Appearance Colourless oily liquid; hygroscopic
platelets when solid
Density 1.099 g/cm
3
Melting point 24â26 °C
Boiling point 242 °C (468 °F; 515 K)
Acidity (pKa) pKBH
+
= 5.14
Other name Benzo[c]pyridine, 2-benzazine
PHYSICAL PROPERTIES
31. The PomeranzâFritsch reaction provides an efficient method for the preparation
of iso-quinoline.
This reaction uses a benzaldehyde and amino-acetoaldehyde diethyl acetal,
which in an acid medium react to form iso-quinoline.
Alternatively, benzylamine and a glyoxal acetal can be used, to produce the
same result using the Schlittler-MĂźller modification.
1. POMERANZâFRITSCH REACTION
32. First the benzalamino-acetal 1 is built by the condensation of benzaldehyde and a 2,2-
dialkoxyethylamine. After the condensation a hydrogen-atom is added to one of the alkoxy
groups. Subsequently, an alcohol is removed. Next, the compound 2 is built. After that a second
hydrogen-atom is added to the compound. In the last step a second alcohol is removed and the
bicyclic system becomes aromatic.
MECHANISM
33. The BischlerâNapieralski reaction is an intramolecular electrophilic aromatic substitution reaction that
allows for the cyclization of β-aryl-ethyl amides or β-aryl-ethyl carbamates.
The reaction is most notably used in the synthesis of dihydro iso-quinolines, which can be
subsequently oxidized to iso-quinolines.
2. BISCHLERâNAPIERALSKI REACTION
34. Mechanism I involves a dichloro-phosphoryl imine-ester intermediate, while Mechanism II involves a
nitrilium ion intermediate (both shown in brackets).
This mechanistic variance stems from the ambiguity over the timing for the elimination of
the carbonyl oxygen in the starting amide.
In Mechanism I, the elimination occurs with imine formation after cyclization; while in Mechanism II,
the elimination yields the nitrilium intermediate prior to cyclization.
Currently, it is believed that reaction conditions affect the prevalence of one mechanism over the other
(see reaction conditions).
In certain literature, Mechanism II is augmented with the formation of an imidoyl chloride intermediate
produced by the substitution of chloride for the Lewis acid group just prior to the nitrilium ion.
Because the dihydro iso-quinoline nitrogen is basic, neutralization is necessary to obtain the deprotonated
product.
MECHANISM
37. The reactions of iso-quinoline are closely parallel to those of quinoline.
Iso-quinoline reacts with strong mineral acids to form salts.
Iso-quinoline is a stronger base than quinoline.
1. Alkylation and acylation occur on nitrogen
2. Reactions of electrophilic and nucleophilic substitution
3. Reduction reactions
4. Oxidation reactions
CHEMICAL REACTION
39. Similarly to quinoline electrophilic substitution reactions occur mainly in the 5or 8 position of iso-quinoline
2. Reactions of electrophilic and nucleophilic substitution
42. Oxidation of iso-quinoline with alkaline permanganate solution yields a mixture of phthalic acid and pyridine3,4-
dicarboxylic acid.
4. Oxidation reactions
43. 1. Anasthetics, dimethisoquin is one example.
â˘2. antihypertension agents, such
as quinapril and debrisoquine (all derived from
1,2,3,4-tetrahydroisoquinoline).
3. antiretroviral agents, such as saquinavir with an
iso-quinolyl functional group,
4. vasodilators, a well-known example, papaverine,
shown below.
APPLICATION
44. Quinoline & Iso-quinoline both have
i. Have basic, pyridine like nitrogen atoms, which undergo electrophilic substitutions.
ii. Are less reactive toward electrophilic substitution than benzene because of the nitrogen atom that
withdraws electrons from the ring.
iii. Electrophilic substitution occurs on the benzene ring rather than on the nitrogen-containing pyridine
ring and a mixture of substitution products is obtained.
In quinoline and iso-quinoline the N-atom withdrawn electron in pyridine
ring thus few are available for Electrophilic Aromatic Substitution (EAS),
therefore E+ prefers to go to benzene.
REACTIVITY OF QUINOLINE & ISO-QUINOLINE
46. INTRODUCTION
Indole is an aromatic heterocyclic organic compound with formula C8H7N.
It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-
membered pyrrole ring.
Indole is widely distributed in the natural environment and can be produced by a variety of bacteria.
Indole is a solid at room temperature.
It occurs naturally in human feces and has an intense fecal odour.
At very low concentrations, however, it has a flowery smell, and is a constituent of many perfumes.
It also occurs in coal tar.
48. BASICITY
Unlike most amines, indole is not basic: just like pyrrole, the aromatic character of the ring means that
the lone pair of electrons on the nitrogen atom is not available for protonation.
Strong acids such as hydrochloric acid can, however, protonate indole.
Indole is primarily protonated at the C3, rather than N1, owing to the enamine-like reactivity of the
portion of the molecule located outside of the benzene ring.
The protonated form has a pKa of â3.6. The sensitivity of many indolic compounds (e.g., tryptamines)
under acidic conditions is caused by this protonation.
49. PHYSICAL PROPERTIES
Chemical
formula
C8H7N
Molar mass 117.151 g¡molâ1
Appearance White solid
Odour Feces or jasmine like
Density 1.1747 g/cm3, solid
Melting point 52 to 54 °C (126 to 129 °F;
325 to 327 K)
Boiling point 253 to 254 °C (487 to
489 °F; 526 to 527 K)
Solubility in
water
0.19 g/100 ml (20 °C)
Soluble in hot water
Acidity (pKa) 16.2 (21.0 in DMSO)
Basicity (pKb) 17.6
51. 1. FISCHER INDOLE SYNTHESIS
The Fischer indole synthesis is a chemical reaction that produces the aromatic heterocycle indole from a
(substituted) phenyl hydrazine and an aldehyde or ketone under acidic conditions.
The choice of acid catalyst is very important.
Brønsted acids such as HCl, H2SO4, polyphosphoric acid and p-toluene sulfonic acid have been used
successfully.
52. MECHANISM
The reaction of a (substituted) phenyl hydrazine with a carbonyl (aldehyde or ketone) initially forms
a phenylhydrazone which isomerizes to the respective enamine (or 'ene-hydrazineâ).
After protonation, a cyclic [3,3]-sigma tropic rearrangement occurs producing an imine.
The resulting imine forms a cyclic amino-acetal (or aminal), which under acid catalysis eliminates NH3,
resulting in the energetically favourable aromatic indole.
Isotopic labelling studies show that the aryl nitrogen (N1) of the starting phenyl hydrazine is incorporated
into the resulting indole.
54. 2. MADELUNG SYNTHESIS
The Madelung synthesis is a chemical reaction that produces (substituted or unsubstituted) indoles by
the intramolecular cyclization of N-phenyl amides using strong base at high temperature.
55. MECHANISM
The reaction begins with the extraction of a hydrogen from the nitrogen of the amide substituent and the extraction
of a benzylic hydrogen from the substituent ortho to the amide substituent by a strong base.
Next, the carbanion resulting from the benzylic hydrogen extraction performs a nucleophilic attack on
the electrophilic carbonyl carbon of the amide group. When this occurs, the pi-bond of the amide is converted into
a lone pair, creating a negatively charged oxygen.
After these initial steps, strong base is no longer required and hydrolysis must occur.
The negatively charged nitrogen is protonated to regain its neutral charge, and the oxygen is protonated twice to
harbor a positive charge in order to become a good leaving group.
A lone pair from the nitrogen forms a pi-bond to expel the positively charged leaving group, and also causes the
nitrogen to harbor a positive charge.
The final step of the reaction is an elimination reaction (specifically an E2 reaction), which involves the extraction
of the other hydrogen that was once benzylic, before the bicyclic compound was formed, whose electrons are
converted into a new pi-bond in the ring system.
This allows the pi-bond formed by nitrogen in the preceding step to be converted back into a lone pair on nitrogen
to restore nitrogen's neutral charge.
59. 2. ELECTROPHILIC SUBSTITUTION
The most reactive position on indole for electrophilic aromatic substitution is C3, which is
10000000000000 times more reactive than benzene.
For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid
tryptophan. VilsmeierâHaack formylation of indole will take place at room temperature exclusively at C3.
Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole
with dimethylamine and formaldehyde. It is the precursor to indole-3-acetic acid and synthetic
tryptophan.
61. 3. Oxidation of indole
Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromo
succinimide will selectively oxidize indole 1 to oxindole (4 and 5).
The nitrogen containing ring of many substituted
indoles can be opened by the action of per-oxy acid
and ozone .
PhC 2O OH
O3 , H2ON
H
R
R'
COR
NHCOR'
PhCO2OH
O3 , H2ON
H
COH
NHCOH
63. 5. MANNICH REACTION
Indole undergo Mannich reaction with formaldehyde and dimethyl amine to give 3 â dimethylamine
indole.
O
HCl
N
H
H
+ H-C- H + HN
N
H
CH2 - NCH3
CH3 H2O
CH3
CH3
3 - dimethylamino methylindole
-
66. 1. https://www.researchgate.net/publication/325080072_UNIT_-V_Heterocyclic_Chemistry_Quinoline_Isoquinoline_and_Indole
2. https://en.wikipedia.org/wiki/Quinoline
3. Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The
Royal Society of Chemistry. 2014. pp. 4, 211. doi:10.1039/9781849733069-FP001. ISBN 978-0-85404-182-4. The name
âquinolineâis a retained name that is preferred to the alternative systematic fusion names â1-benzopyridineâ or
âbenzo[b]pyridineâ.
4. Brown, H.C., et al., in Baude, E.A. and Nachod, F.C., Determination of Organic Structures by Physical Methods, Academic
Press, New York, 1955.
5. Shang, XF; Morris-Natschke, SL; Liu, YQ; Guo, X; Xu, XS; Goto, M; Li, JC; Yang, GZ; Lee, KH (May 2018). "Biologically
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Jun-Cai; Zhang, Ji-Yu; Lee, Kuo-Hsiung (September 2018). "Biologically active quinoline and quinazoline alkaloids part
II". Medicinal Research Reviews. 38 (5): 1614â1660. doi:10.1002/med.21492. PMC 6105521. PMID 29485730.
7. F. F. Runge (1834) "Ueber einige Produkte der Steinkohlendestillation" (On some products of coal distillation), Annalen der
Physik und Chemie, 31 (5) : 65â78 ; see especially p. 68: "3. Leukol oder WeissĂśl" (3. White oil [in Greek] or white oil [in
German]). From p. 68:"Diese dritte Basis habe ich Leukol oder WeissĂśl genannt, weil sie keine farbigen Reactionen
zeigt." (This third base I've named leukol or white oil because it shows no color reactions.)
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(1843) "Chemische Untersuchungen der organischen Basen im Steinkohlen-TheerĂśl" (Chemical investigations of organic bases in
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Alkylation of Quinoline and Isoquinoline with Carboxylic Acids". Synthesis. 1975 (10): 650â652. doi:10.1055/s-1975-
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13. Xu, L.; Lam, K. H.; Ji, J.; Wu, J.; Fan, Q.-H.; Lo, W.-H.; Chan, A. S. C. Chem. Commun.2005, 1390.
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15."QUINOLINE (BENZOPYRIDINE)". Chemicalland21.com. Retrieved 2012-06-14.
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p. 759.
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Academic Press, New York, 1955.
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20. Harris, J.; Pope, W.J. "isoQuinoline and the isoQuinoline-Reds" Journal of the Chemical Society (1922) volume 121, pp. 1029â1033.
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