Synthesis and Spectroscopy Studies

of By-products of Chloroquinaldol
LUCIA PINTILIE1*, MIHAELA DEACONU1, AMALIA STEFANIU1, CONSTANTIN TANASE1, MIRON TEODOR CAPROIU2
National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Av., 74373, Bucharest, Romania
2
Organic Chemistry Center C.D.Nenitescu, 202 B Splaiul Independentei, 060023, Bucharest, Romania

Chlorquinaldol (5,7-dichloro-2-methyl-quinolin-8-ol) presents a significant attention due to its antibacterial

activity, antifungal activity, trichomonal and keratoplastic effect and due to the fact it is an important
intermediate for the preparation of some biologically active compounds. In the process of the preparation of
the chlorquinaldol, by chlorination of 8-hydroxyquinaldine using as chlorinating agent, chlorine gas, have
been obtained 5-chloro-8-hydroxyquinaldine and 5,6,7-trichloro-8-hydroxyquinaldine, by-products which
contaminate the final compound. This paper presents experimental data regarding the synthesis of byproducts of chlorquinaldol. The quinoline compounds have been analyzed through physico-chemical
techniques (1H-NMR, 13C-NMR, FT IR, UV-Vis). Molecular, topological, conformational characteristics and
quantitative structure-activity/property relationships on 3D quinolones optimized structure have been
calculated using Spartan 14 Software. For each structure of the analyzed class, the 3D structure used for
calculations was generated and its geometry has been optimized by energy minimization, in order to obtain
the most stable conformer. NMR and IR spectra of the quinoline compounds have been calculated with
Spartan 14 software. After analyzing the experimental and calculated spectra (1H-NMR, 13C-NMR, IR) the
correlation between experimental and calculated data has been observed
Keywords: quinoline, hydroxyquinaldine, chlorquinaldol, chlorination, computational studies,
spectroscopy studies

The quinolines are N-heterocyclic compounds with

many applications in pharmaceutical and agrochemical
industries [1-4].
One of the quinoline compound, 5,7-Dichloro-2-methyl8-hydroxy-quinoline, (chlorquinaldol) has received
significant attention in the last years, due of his biological
activity(antibacterial activity, antifungal activity,
trichomonal and keratoplastic effect) and due to the fact it
is an important intermediate for the synthesis of a variety
of compounds with biological activity [3,5].
5,7-Dichloro-2-methyl-8-hydroxy-quinoline (chlorquinaldol) can be prepared (scheme 1) by regioselective
conversion of the corresponding N-oxide ( 5,7-dichloro-8hydroxyquinoline-1-oxide). By coupling reaction of the
heterocyclic N -oxide with Grignard reagent (methylmagnesium chloride) have been obtained regioselectively
and in good yield the final product [6].

Another method of preparation of the 5,7-Dichloro-2methyl-8-hydroxy-quinoline is the chlorination of the 8hydroxyquinaldine with chlorine, in the presence of
hydrochloric acid [7,8], in the presence of formic acid [9],
in the presence of iodine and chloroform [10].
Fiedler H [11] report the chlorination with tert butylhypochlorit in carbon tetrachloride of the 8hydroxyquinaldine or of the 7-chloro-8-hydroxyquinaldine.
In the case of the chlorination of the 8-hydroxyquinaldine
with chlorine yield by-products: mono- and polychlorinated
compounds (scheme 2).
Monochlorinated compound : 5-chloro-2-methyl-8hydroxy-quinoline can be prepared (scheme 3) by
regioselective conversion of the corresponding N-oxide(5chloro-8-hydroxyquinoline-1-oxide).By coupling reaction of
the heterocyclic N -oxide with Grignard reagent

Scheme 1

* email: lucia.pintilie@gmail.com
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613

synthesized be chlorination the copper(II) chelate of 8hydroxyquinaldine with N-chloro-succinimide[19].

For the compound: 5,6,7-Trichloro-8-hydroxyquinaldine,
we found only one indication about the preparation. This
compound have been synthesized by chlorination of 8hydroxyquinaldine in N,N-dimethylformamide [22].
This paper presents synthesis and spectroscopy studies
of the by-products which results from the chlorination of
the 8-hydroxyquinaldine.

Scheme 2

(methylmagnesium chloride) have been obtained

regioselectively and in good yield the final product [6].
Another method of preparation of the 5-chloro-2-methyl8-hydroxy-quinoline is the chlorination of the 8hydroxyquinaldine with chlorine gas, in the presence of
hydrochloric acid [12], in the presence of iodine and
hydrochloric acid [13], or chlorination with N-chlorosuccinimide [21]. Talekar and collective [14] reports
synthesis of 5-chloro-8-hydroxyquinaldine by heating 5chloro-7-iodo-8-hydroxyquinaldine in the presence of
triethylamine and by hydrolysis and deiodination of 5-chloro7-iodo-2-methylquinolin-8-yl-ethanoate in the presence of
pyridine/water.
5-Chloro-2-methyl-8-hydroxy-quinoline can be also
preparated by condensation of 2-amino-4-chlorophenol
with crotonaldehyde, (Skraup, Doebner-Miller synthesis
[15,16], condensation with paraldehyde [17,18],or
chlorination of 2-amino-4-chlorophenol (Sandmeyer
reaction) [20].
5-Chloro-2-methyl-8-hydroxy-quinoline have been

Experimental part
Melting points were determined in opened capillary on
Melting point apparatus OptiMelt and are uncorrected. 1Hand 13C-NMR spectra were recorded in CDCl3, DMSO-d6
and trifluoroacetic acid, on two instruments Varian, Varian
Gemini 300 BB (operating at 300 MHz for proton and 75
MHz for carbon) and UNITY 400 Plus(operating at 400 MHz
for proton and 100 MHz for carbon). Tetramerthylsilane as
internal standard was the reference for the chemical shifts.
All chemical shifts are given in the delta scale (ppm vs
internal TMS). FT IR was recorded on an instrument Bruker
Vertex 70 with optical diamond.
5-Chloro-8-hydroxyquinaldine (5-chloro-2-methyl-8hydroxy-quinoline)
5-Chloro-8-hydroxyquinaldine has been preparated by
chlorination of 8-hydroxyquinaldine using as chlorinating
agent, chlorine gas. The appropriate amount of chlorine
gas was bubbled into a solution obtained by dissolving the
8-hydroxyquinaldine in concentrated hydrochloric acid. The
end of the reaction was determined by weighing.
The structure of this compound has been confirmated
by:1H-NMR (fig. 1) (table 1),13C-NMR(fig.4) (table 2), FTIR
(fig.7) (table 3), UV-Vis (fig. 10). (p.t. o = 65.9-67.4 oC
(methanol))
5,7-Dichloro-8-hydroxyquinaldine (5,7-dichloro-2methyl-8-hydroxy-quinoline)
5,7-Dichloro-8-hydroxyquinaldine has been preparated
by chlorination of 8-hydroxyquinaldine using as chlorinating
agent, chlorine gas. The appropriate amount of chlorine
gas was bubbled into a solution obtained by dissolving the
8-hydroxyquinaldine in concentrated hydrochloric acid. The
end of the reaction was determined by weighing.
The structure of this compound has been confirmated
by: 1H-NMR(fig.2) (table 1),13C-NMR(fig.5) (table 2), FTIR
(fig.8)(table 3), UV-Vis (fig. 10). (p.t.o = 109.8-113.1oC
(acetone))

Scheme 3

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REV.CHIM.(Bucharest) 67No. 4 2016

Fig. 1 1H-NMR spectrum of 5-Chloro-8-hydroxyquinaldine

1a- experimental spectrum; 1b-calaculated spectrum

Fig.2. 1H-NMR spectrum of 5,7-Dichloro-8-hydroxyquinaldine

2a- experimental spectrum; 2b-calculated spectrum

Fig. 3

1
H-NMR spectrum of 5,6,7-Trichloro-8-hydroxyquinaldine
3a- experimental spectrum; 3b-calculated spectrum

Table 1
CALCULATED AND MEASURED
1
H-NMR SPECTRA

5,6,7-Trichloro-8-hydroxyquinaldine (5,6,7trichloro-2-methyl-8-hydroxy-quinoline)
5,6,7-Trichloro-8-hydroxyquinaldine has been preparated
by chlorination of 8-hydroxyquinaldine using as chlorinating
agent, chlorine gas. The appropriate amount of chlorine
REV.CHIM.(Bucharest)67 No. 4 2016

gas was bubbled into a solution obtained by dissolving the

8-hydroxyquinaldine in concentrated hydrochloric acid. The
end of the reaction was determined by weighing.
The structure of this compound has been confirmated
by 1H-NMR (fig.3)(table 1),13C-NMR (fig.6) (table 2), FTIR

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615

Fig. 4. 13C-NMR spectrum of 5-Chloro-8-hydroxyquinaldine

4a- experimental spectrum; 4b-calculated spectrum

Fig.5. 13C-NMR spectrum of 5,7-Dichloro-8-hydroxyquinaldine

5a- experimental spectrum; 5b-calculated spectrum

Fig.6. 13C-NMR spectrum of 5,6,7-Trichloro-8-hydroxyquinaldine

6a- experimental spectrum; 6b-calculated spectrum

(fig.9) (table 3) and UV-Vis (fig.10). (p.t.o = 165.1-165.9oC

(methanol))

Computational studies
Molecular, topological, conformational characteristics
and quantitative structure-activity/property relationships
(QSAR/ QSPR) on 3D quinolones optimized structure were
calculated using Spartan 14 Software.
Results and disscusions
Experimental studies for synthesis of: 5-Chloro-8hydroxyquinaldine (5-chloro-2-methyl-8-hydroxy-quinoline),5,7-Dichloro-8-hydroxyquinaldine (5,7-dichloro-2methyl-8-hydroxy-quinoline) and 5,6,7-Trichloro-8hydroxyquinaldine (5,6,7-trichloro-2-methyl-8-hydroxyquinoline) are presented.
The quinoline compounds have been analyzed through
physico-chemical techniques (1H-NMR, 13C-NMR, FT IR,
UV-VIS).
H-NMR spectra have been confirmed the structure of
the compounds proposed to be synthetisized by
chlorination of the 8-hydroxyquinaldine with chlorine gas
in chlorhidic acid.
In the case of the monochlorinated compound it was
observed the absence of the signal of the proton in 5
position of the quinoline ring (fig. 1a, table 1).
In the case of the chlorchinaldol (5, 7-Dichloro-8hydroxyquinaldine) it was observed the absence of the
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signals of the protons in 5 and 7 positions of the quinoline

ring (fig. 2a, table 1).
For the 5,6,7-Trichloro-8-hydroxyquinaldine) it was
observed the absence of the signals of the protons in 5, 6
and 7 positions of the quinoline ring (fig. 3a, table 1).
Structure of the quinoline compounds synthesized in
the study has been also confirmed by C-NMR spectra (fig.
4a, 5a, 6a, table 2).
In the figure 6, 8 and 9 are presented the FTIR spectra of
the studied compounds: 5-Chloro-8-hydroxyquinaldine, (fig
6a), 5,7-Dichloro-8-hydroxyquinaldine (fig. 8a) and 5,6,7Trichloro-8-hydroxyquinaldine (fig. 9a).
In table 3 are presented some characteristic bands of
studied molecules.
The introduction of chlorine atom in the 8-hydroxy
quinalidine ring was has been also proved in by UV
spectrum (fig.10).
UV absorption spectra study was carried out using
solutions with concentration of 10 m g/mL in methanol.
Interpretation of the UV absorption spectrum of 5-Chloro8-hydroxyquinaldine (ClHQ) has been made in comparison
with that of the 8-hydroxyquinaldine (2-methyl-8-hydroxyquinoline)(8HQ). The presence of the quinoline nucleus
determines in methanol the appearance of electronic
transitions in the field of 220-280 nm. The introduction of
chlorine atom in 5 position produces a batocroma
displacement of the entire spectrum.

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REV.CHIM.(Bucharest) 67No. 4 2016

Table 2
CALCULATED AND
MEASURED 13C-NMR
SPECTRA

Fig. 7. FTIR spectrum of 5-Chloro-8-hydroxyquinaldine

7a- experimental spectrum ; 7b-calculated spectrum

Fig.8. FT-IR spectrum of 5,7-Dichloro-8-hydroxyquinaldine

8a- experimental spectrum; 8b-calculated spectrum

Fig.9 FT-IR spectrum of 5,6,7-Trichloro-8-hydroxyquinaldine

9a- experimental spectrum; 9b-calculated spectrum

The introduction of the second chlorine atom in the 7

position of quinoline nucleus produces also a batocroma
displacement of the entire spectrum. Interpretation of the
UV absorption spectrum of 5,7-Dichloro-8-hydroxy-

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quinaldine (chlorquinaldol) (DiClHQ) has been made in

comparison with that of 5-Chloro-8-hydroxyquinaldine
(ClHQ).

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617

Table 3
CALCULATED AND
MEASURED IR SPECTRA

The introduction of the third chlorine atom in the 6 position of quinoline nucleus produces also a batocroma
displacement of the entire spectrum. Interpretation of the UV absorption spectrum of 5,6,7-trichloro-8-hydroxy-quinaldine
(5,6,7TriClHQ). Has been made in comparison with that of chlorchinaldol.

Fig. 10. Claculated and

measured UV-Vis
aborption spectra

Table 4
CALCULATED UV-Vis SPECTRA

Computational studies
In addition, a study of the molecular and structural
characteristics and properties has been achieved using
Spartan 14 software. A computational study to compare
molecular properties, QSAR properties and mechanics
calculations for quinoline compunds, has been conducted
using Spartan 14 Software. For each structure of the
analyzed class, the 3D structure used for calculations was
generated and its geometry has been optimized by energy
minimization, in order to obtain the most stable conformer
(table 5).
For these conformers, the most important topological
and conformational characteristics has been calculated:
weight, energy of solvation, dipole moment, energy of the
618

frontier molecular energies (fig. 11), HOMO-LUMO gap

(table 5). The HOMO-LUMO gap is related to kinetic stability
or chemical reactivity. The higher value of HOMO-LUMO
gap, for all three quinolines of the study, refers to chemically
stable molecules [23].
We have been calculated the important structural
parameters: bond lenght (table 6), dihedral angles (the
value of all dihedral angles is zero, it indicates that the all
atoms are placed in the same plane).
H-NMR (fig. 1b. 2b. 3b), C-NMR (fig. 4b, 5b, 6b), IR (fig.
7b, 8b, 9b) and UV (fig.10b) spectra of the quinoline
compounds have been calculated with Spartan 14
software.
After analyzing the experimental and calculated spectra

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REV.CHIM.(Bucharest) 67No. 4 2016

Table 5
ANALYZED
STRUCTURE

Fig. 11. Frontier

molecular orbitals for
quinoline compounds

Table 6
SELECTED BOND
LENGTHS

(H-NMR, C-NMR, IR, UV) the correlation between

experimental and calculated data has been observed
(table 1-4).
REV.CHIM.(Bucharest)67 No. 4 2016

Conclusions
In conclusion, we have synthesized the by-products of
chlorquinaldol : 5-Chloro-8-hydroxyquinaldine and 5,6,7-

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619

Trichloro-8-hydroxyquinaldine.The quinoline compounds

have been analyzed through physico-chemical techniques
(1H-NMR, 13C-NMR, FT IR, UV-Vis).
Molecular, topological and conformational
characteristics on 3D quinolines optimized structure have
been calculated using Spartan 14 Software. For each
structure of the analyzed class, the 3D structure used for
calculations was generated and its geometry has been
optimized by energy minimization, in order to obtain the
most stable conformer.
NMR, IR and UV spectra of the quinoline compounds
have been calculated with Spartan 14 software. The
correlation between experimental and calculated data has
been observed after analyzing the experimental and
calculated spectra (1H-NMR, 13C-NMR, IR, UV).
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