Synthesis of 8-hydroxyquinoline chalcones: Trans configuration, intramolecular hydrogen bonds, bromination, and antifungal activity

Article abstract of DOI:10.4067/S0717-97072012000300019

Nine (8-Hydroxyquinolin-5-yl)-arylpropenones were synthesized and their structures demonstrated by IR and NMRspectroscopy. These molecules showed transconfiguration and strong intramolecular hydrogen bonding; in the IR spectra of 5-formyl-8-hydroxyquinoline, 5-acetyl-8-hydroxyquinoline, 1-(8-hydroxyquinolin-5-yl)-3-phenylprop-2-en-1-one and 3-(8-hydroxyquinolin-5- yl)-1-phenylprop-2-en-1-one in CHCl3, besides the known intermolecular hydrogen band (～3180 cm^-1), we identified the intramolecular hydrogen band OH...N (3460 cm^-1); the hydrogen bond peaks shifted to low frequency in proton-donor solutions such as phenol and acetic acid (with respect to 8-hydroxyquinoline) and the bonds were broken in trifluoroacetic acid solutions, due to OH protonation; the apolar solvent CCl4 and electrophilic substituents in position 5 in the quinoline ring, limited the formation of the intermolecular hydrogen bonds and, therefore, shifted the ～3460 cm^-1 intramolecular hydrogen band to lower frequencies and made it stronger and sharper. The bromination of 3-(8-hydroxyquinolin-5-yl)-1-(4- tolyl) prop-2-en-1-one occurred on the activated quinoline fragment, producing monobromo and tetrabromo derivatives, instead of bromination on the aliphatic double bond. Three chalcones tested showed strong antifungal activity in vitro.

Full text of DOI:10.4067/S0717-97072012000300019

J. Chil. Chem. Soc., 57, Nº 3 (2012)
SYNTHESIS OF 8-HYDROXYQUINOLINE CHALCONES: TRANS CONFIGURATION, INTRAMOLECULAR
HYDROGEN BONDS, BROMINATION, AND ANTIFUNGAL ACTIVITY
ALONSO J. MARRUGO-GONZÁLEZ,1 VALERIE D. ORLOV,2 ROBERTO FERNANDEZ-MAESTRE1
1Programa de Química, Universidad de Cartagena, Cartagena, Colombia
2Karazin Kharkov National University, Organic Chemistry Department, Svobody sq. 4, 61077 Kharkov, Ukraine
(Received: March 1, 2012 - Accepted: March 8, 2012)
ABSTRACT
Nine (8-Hydroxyquinolin-5-yl)-arylpropenones were synthesized and their structures demonstrated by IR and NMRspectroscopy. These molecules
showed transconfiguration and strong intramolecular hydrogen bonding; in the IR spectra of 5-formyl-8-hydroxyquinoline, 5-acetyl-8-hydroxyquinoline,
1-(8-hydroxyquinolin-5-yl)-3-phenylprop-2-en-1-one and 3-(8-hydroxyquinolin-5-yl)-1-phenylprop-2-en-1-one in CHCl3, besides the known intermolecular
hydrogen band (~3180 сm-1), we identified the intramolecular hydrogen band ОН...N (3460 сm-1); the hydrogen bond peaks shifted to low frequency in proton-donor
solutions such as phenol and acetic acid (with respect to 8-hydroxyquinoline) and the bonds were broken in trifluoroacetic acid solutions, due to OH protonation;
the apolar solvent CCl4 and electrophilic substituents in position 5 in the quinoline ring, limited the formation of the intermolecular hydrogen bonds and, therefore,
shifted the ~3460 сm-1 intramolecularhydrogenband to lower frequencies and made it stronger and sharper. The bromination of 3-(8-hydroxyquinolin-5-yl)-1-(4-
tolyl) prop-2-en-1-one occurred on the activated quinoline fragment, producing monobromo and tetrabromo derivatives, instead of bromination on the aliphatic
double bond. Three chalcones tested showed strong antifungal activity in vitro.
Keywords: 8-hydroxyquinoline, chalcones, bromination, antifungal activity
2. Synthesis of 5-acetyl-8-hydroxyquinoline (3)
INTRODUCTION
A solution of 43.5 g (0.300 moles) of 8-hydroxyquinoline in 40 g of
nitrobenzene was added with 25.1 g (0.320 moles) of acetic chloride and
produced a yellow precipitate. The mixture was stirred and 100 g (0.75 mol)
of AlCl3 was added to dissolve the precipitate. This solution was heated to 70
°С for 12 hours, cooled and crushed ice and 100 ml of 10% HCl was added,
which formed two phases: water and nitrobenzene. Nitrobenzene was removed
by steam distillation and the aqueous phase was allowed to stand for 8 hours
which precipitated the hydrochloride of 3; the precipitate was dried, dissolved
in water, and neutralized with 0.1 M solution of sodium acetate to reprecipitate
3 which was later crystallized with distilled water.
a,b-unsaturated ketones containing aromatic or heterocyclic radicals
(chalcones) have attracted researcher attention mainly due to their high
reactivity, which allows the synthesis of new organic compounds.1,2 Chalcone
derivatives have been found with high efficient photoactivity such as
luminophores, photo-, thermo-, and electrochromic, compounds and dyes for
lasers and others with a variety of physiological activity.3 Studies have increased
on cyclocondensation reactions involving a,b- unsaturated ketones and nitrogen
nucleophiles. These reactions are the best method for the synthesis of azoles,
azinopyridines, and pyrimidines that are similar to many natural compounds
due to their conjugated system with two nonequivalent electrophilic centers
that determine the regioselectivity of these reactions.4 The combination of
these electrophilic centers, the hydroxyquinoline and the highly reactive enone
fragments, opens a wide perspective for the synthesis of organic compounds
with chelating properties.5,6 The synthesis of 5-formyl- and 5-acetyl-8-
hydroxyquinoline has been described;7,8 the reaction of Reymon and Thiman
is traditionally used to obtain 5-formyl-8-hydroxyquinoline,5,7 but this method
has poor reproducibility, possibly because of the tendency of the product to
form chelates. On the other hand, 5-formyl- and 5-acetyl-8-hydroxyquinoline
easily condense with substituted benzaldehydes and acetophenones in basic-
ethanolic medium producing chalcones with high yields.
3. Synthesis of 3-(8-hydroxyquinolin-5-yl)-1-phenylprop-2-en-1-one
(4)
A solution of 2.80 g (0.0161 moles) of 5-formyl-8-hydroxyquinoline in
50 ml of hot concentrated hydrochloric acid was added with 4.00 g (0.0333
mol) of acetophenone; the solution was stirred for 8 hours and a precipitate
(4) was obtained, which was washed with ether, neutralized with aqueous 0.1
M sodium acetate, and recrystallized from ethanol. Compounds 5-10 were
obtained likewise but changing acetophenone for the corresponding reagent
(Table 1).
4. Synthesis of 1-(8-hydroxyquinolin-5-yl)-3-phenylprop-2-en-1-one
(11)
A solution of 0.370 g (0.00214 moles) of 5-acetyl-8-hydroxyquinoline,
0.210 g (0.00198 moles) of benzaldehyde and 5 ml of concentrated HCl was
left for 6 hours in a closed flask stirring every half hour by opening the flask lid.
The precipitate obtained was filtered, dissolved in water and neutralized with
0.1 M sodium acetate to reprecipitate 11. Compounds 12-17 were obtained
likewise but changing benzaldehyde for the corresponding reagent (Table 1).
5. Bromination of 3-(8-hydroxyquinolin-5-yl)-1-(4-tolyl) prop-2-en-1-
one (5)
Literature reports on a,b- unsaturated ketones derived from
8-hydroxyquinoline are scarce;5,7,9-11 there are reports on derivatives of 5-acetyl-
8-hydroxyquinoline and the synthesis of a series of 2-pyrazoline, oxazolines,
pyridines, and pyrimidines.11 This work investigates chalcones derived from
5-formyl- and 5-acetyl-8-hydroxyquinoline, their configuration, interaction
with proton donors, bromination reaction, and biological activity.
EXPERIMENTAL
A solution of 200 mg of 5 in 10 ml of chloroform was added with a solution
of 8 ml of chloroform with 280 mg of bromine, stirring at 50 °С. Then more
bromine solution was added until the solution was colored brown; a yellow
product precipitated (19) which was filtered and washed with hot ethanol. The
filtrate plus ethanol were mixed and a red crystal (18) precipitated by shaking.
6. Characterization of the chalcones
The monitoring of all reactions was performed by thin layer
chromatography. The chromatograms were developed on Silufol UV-254
plates, using acetic acid as eluent; UV light or iodine were used to reveal the
plates. All reagents were analytical grade (Merck, Darmstadt, Germany).
1. Synthesis of 5-formyl-8-hydroxyquinoline (2)
A solution of 20.32 g (0.140 moles) of 8-hydroxyquinoline in 80 ml of
ethanol was mixed with 50 ml of 80% aqueous solution of NaOH and refluxed
at 80ºC for 1 hour; then, 27.46 g (0.2300 moles) of chloroform were added
dropwise and the mixture refluxed at 80 ºC for 12 hours. Later, the excess
of chloroform and ethanol was evaporated, and the residue was diluted with
600 ml of water and acidified with HCl 1% until complete precipitation.
The complex mixture on the precipitate was dried, and 2 was extracted with
n-hexane.
1
The chalcones and their precursors were identified by H NMR and IR
spectroscopy. NMR spectra were taken on a Varian Mercury VX-200 (200
МHz) in DMSO-d6 solutions. IR spectra were taken on an IR-75 Specord
instrument. Melting temperatures were determined in glass capillaries.
Elemental analysis was performed to determine nitrogen (bromine indirectly)
by the Dumas method.12 Potential biological activity was calculated with the
computer system PASS (Prediction of Activity Spectra for Substances). PASS
provides simultaneous prediction of several hundreds of biological activity
e-mail: rfernandezm@unicartagena.edu.co
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J. Chil. Chem. Soc., 57, Nº 3 (2012)
types for any drug-like compound. The prediction is based on the analysis of
structure-activity relationships of the training set including more than 30000
known biologically active compounds.13 Biological activity in-vitro was
calculated for three chalcones in the Universidad del Valle (Colombia) using a
broth microdilution method to determine the minimum inhibitory concentration
(NCCLS, 2003).14
RESULTS AND DISCUSSION
Nine new chalcones were synthesized (5-10, 12, 16, 18 and 19, Table 1).
The synthesis of 2 and 3 was described long ago,7,8 but we have found difficult to
reproduce reaction yields, especially those of the aldehyde. Compounds 2 and
3 were easily condensed with substituted benzaldehydes and acetophenones
in basic ethanolic medium producing chalcones 4-17 with 60-80% yields
(Scheme 1). The yield of the synthesis of 2 was increased from 10.5% 7 to 18%.
Nitrogen analyses corresponded to those calculated. Melting temperatures
for our compounds had no significant differences from those in the literature6,8
(Table 1), which corroborates the identification of those already reported. The
structures of 4-17 were demonstrated by IR and NMR. The IR spectra showed
the covalent vibrational bands associated with the OH groups (~ 3300 cm-1),
carbonyl groups (1645-1655 сm-1), and the medium intensity band often at 1100
сm-1, characteristic of the deformation vibration of С-Н bonds of trans-vinylene
groups,15 which indicates a trans configuration for the vinylene protons.
Scheme 1
Table 1. Physico-chemical properties of the a,b-unsaturated ketones of the 8-hydroxyquinoline series.
Yield
Compound
R
Formula
Melting Temperature (1)
IR (KВr), cm-1
%/hours(2)
оС
C=O
O-H
3430
3120
2
-
C10H7NO2
173°С
18%
1684
3
4
-
H
C11H9NO2
C18H13NO2
112°С
165
17%
70/8
1659
1656
1656
1652
1644
1652
1652
1652
1652
1652
1648
1652
1652
1656
1660
1656
1656
3270
3304
3175
3188
3312
3288
3288
3250
3320
3320
3156
3284
3316
3308
3312
3312
3416
5
CH3
OCH3
N(CH3)2
Cl
C19H15NO2
162-65
155-7
210
28/7
6
C19H15NO3
70/8
7
C20H18N2O2
C18H12ClNO2
C18H12BrNO2
C18H12N2O4
C18H13NO2
23/15
70/4
8
170-2
186
9
Br
70/10
20/22
60/6
10
11
12
13
14
15
16
17
18
19
NO2
H
205-7
139-40
180
CH3
OCH3
N(CH3)2
Cl
C19H15NO2
79/7
C19H15NO3
188
62/9
C20H18N2O2
C18H12ClNO2
C18H12BrNO2
C18H12N2O4
C19H14NO2Br
C19H11NO2Br4
184
65/11
72/7
185
Br
197-205
217-24
220
70/11
80/17
70/1
NO2
CH3(3)
CH3(4)
240
20/1
(1) 4 (173);9 11 (143-144),9 (102-104);11 13 (193-194);9 14 (191-192),9 (185-186);11 15 (180-181);11 17 (224).9
(2) Yield after recrystallization from ethanol (4-12, 14-19) and methanol (13)/reaction time
(3) Monobromination product of 5: 3-(7-bromo-8- hydroxyquinolin-5-yl)-1-(4-tolyl)prop-2-en-1-one (18)
(4) Tetrabromination product of 5: 3-(3,4,6,7-tetrabromo-8-hydroxyquinolin-5-yl)-1-(4- tolyl)prop-2-en-1-one (19)
1288

J. Chil. Chem. Soc., 57, Nº 3 (2012)
One objective of this research was to study chalcones basicity by measur-
ing the signal change of the hydroxyl group band due to hydroxyl protonation
when adding a proton donor (phenol, trifluoroacetic acid and acetic acid); we
also analyzed the IR spectra of 1-3 to compare with those of the chalcones.
The chelating ability 8-hydroxyquinoline is well known.16 In its IR spec-
trum in KBr,17 8-hydroxyquinoline shows a broad band at ~3179 сm-1. The
IR spectra of compounds 1 and 2 in KBr (Table 2) showed two bands, one
assigned to the intermolecular (~3140 сm-1) and other to the intramolecular
hydrogen bond ОН...N (~3440 сm-1). This intramolecular band has been dem-
onstrated for 8-hydroxyquinoline N-oxide18 and we are demonstrating it for 2-4
and 11. In CCl4, the band at 3140 сm-1 of 1 and 2 disappeared, and the intramo-
lecular band shifted to lower frequencies and became intense and sharp, with
respect to 1, (peak width at half height ~7 cm-1) because CCl is an apolar sol-
vent that limits the formation of intermolecular hydrogen bo4nds; the intensity
of the band at 3416 сm-1 of solutions of 1 in CCl4 increased with concentration.
The bands at ~3140 and ~3440 сm-1 of 3, 4 and 11 in KBr (Table 2) overlapped
into a wide band centered at ~3300 сm-1.
As expected, the intramolecular band increased in intensity and sharpness
in 2, 3, 4 and 11 in CHCl3 (not shown in Table 2) and CCl4 and shifted to low
frequency (~3360 сm-1), with respect to 1; this behavior was probably due to
the increased acidity of the OH group caused by the electroreceptor carbonyl
group in 2, 3, 4 and 11 compared to 1; this group makes the OH hydrogen more
positive which strengthen the intramolecular hydrogen bond.
Таble 2. Frequency of vibrations of CO and OH groups in the IR spectra of a,b-unsaturated ketones of the 8-hydroxyquinoline series in KBr and ССl4 solution
with additions of proton donors and without them.
KBr
CCl4
CCl4 + Phenol
CCl4 + CH3COOH
CCl4 + CF3COOH
γCO
γOH
γCO
gOH
γCO
gOH
γCO
gOH
γCO
gOH
(cm-1)
(cm-1)
(cm-1)
(cm-1)
(cm-1)
(cm-1)
(cm-1)
(cm-1)
(cm-1)
(cm-1)
1689
1675
1630
3453
3160
1
2
3
3416
3366
3359
3416
3363
3356
3419
3363
3356
3070
1692
1675
1630
3430
3120
3426
3089
1684
1659
1689
1669
1689
1669
1689
1669
1689
1675
1630
3433
3092
3270
1685
1645
1635
4
1656
1652
3304
3320
1665
1665
3346
3386
1659
1665
3440
3390
**
**
3440
3296
11
1665
3385
1655
** Not obtained due to solubility problems
The addition of proton donors such as phenol and acetic acid did not
change the IR spectra of 1, 2 and 3. With the addition of trifluoroacetic acid
in CCl , the intramolecular hydrogen bond peak (3440 сm-1) disappeared from
the IR 4spectrum of 1 due to OH protonation, and the intermolecular hydrogen
bond peak shifted to low frequency (~3070 сm-1). With 2 and 3, besides the
intermolecular hydrogen bond peak (3089-3092 сm-1), one appeared between
3426-3433 сm-1, probably caused by the association trifluoroacetic acid-
carbonyl group, which formed a hydroxyl group. In all experiments with
trifluoroacetic acid, we observed a complex spectrum in the region of the
carbonyl group (1630-1692 сm-1), identical for 1, 2 and 3, due to carbonyl
protonation.
It was difficult to add proton donors to chalcones 5-10, 12-17 due to their
low solubility in CCl4 which hindered the interaction with proton donors.
Therefore, Table 2 only shows data for compounds without substitution on the
benzene ring, 4 and 11; these data suggests that the nature of the interaction
of 4-17 with proton donors might be similar to that discussed previously for 2
and 3.
The number of aliphatic and aromatic protons calculated from the area of
the peaks in the spectra (see supplementary material) correlated well with the
number of protons expected from the molecular formulas of the compounds
synthesized. Proton signals, especially the vinyl proton signals, were identified
by comparison with those of 8-hydroxyquinoline (1); vinyl protons appeared
as a pair of well defined doublets with spin-spin coupling constants between
15.3 and 15.9 Hz, which shows the trans configuration and geometry of these
protons relative to each other in chalcones 4-17. We compared the change
in chemical shift of quinoline protons of chalcones 4-17 to the same signals
in compounds 2 and 3; the introduction of the enonic fragment (-C=C-CO-)
produced a signal shift between 0.57 and 1.81 ppm in protons 4H for chalcones
4-10 compared to 2 (Table 3). This shift shows that the double bond was close
to the 4H proton and exerted a strong effect on it. Similarly, when chalcones
11-17, wherein the 4H proton approaches the carbonyl group, are compared
to 3, this effect is minor. This spatial effect is also exerted on the b proton of
the enonic fragment of chalcones 4-10 moving its signal to high field. This
can be explained only if the quinolinic fragment and the double bond had an
anti orientation, i.e. the pyridine fragment is the closest to the enonic b proton.
The bromination of 5 produced 18 and 19, that were substituted on the
quinolinic fragment; using elemental analysis and NMR, 18 was identified as
the 7-bromoderivative (the signal of proton 7 at 7.18 ppm disappeared, Table
3) and 19 was identified as the 3,4,6,7-tetrabromoderivative of 5 (the signals
of protons 3, 4, 6, and 7 at 8.91, 7.66, 8.75, 8.33 and 7.18 ppm, respectively,
disappeared, Table 3); there was not addition of bromine to the C=C double
bond due to the strong activating influence of the 8-hydroxy group on the
quinolinic fragment, which led to replacement of the quinolinic protons
by bromine; the double bond was brominated only after the aromatic ring.
Furthermore, the first proton replaced by bromine was the one in position 7
on the ring, ortho to the hydroxyl group, which is the active position due to
activation by this group.
Biological activity. PASS software was used to calculate the biological
activity; in general, all studied compounds showed theoretical biological
activity; 6 and 13, for example, were found to be mucomembranous protectors,
antiseborrheic,andinhibitorsofaminedehydrogenase,glutathionethiolesterase,
feruloyl esterase, alkane 1-monohydrogenase, and indanol dehydrogenase for
a probability of more than 78%. Antifungal activity was measured in vitro for
5, 12 and 14; the minimal inhibitory concentrations (MIC) in μg/mL for ten
fungi (Table 4) showed antifungal activity for these compounds; compound
14 showed the lowest minimal inhibitory concentrations between these three
compounds.
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J. Chil. Chem. Soc., 57, Nº 3 (2012)
Table 3. NMR spectra of the a,b-unsaturated ketones of the 8-hydroxyquinoline series
d, (ppm)*
Quinolinic fragment
№
enon
aryl
2 Н
8.83
8.96
8.89
8.90
8.91
8.92
8.91
8.93
8.96
9.11
8.92
8.92
8.92
8.86
8.91
8.98
8.99
8.96
9.05
3 Н
7.52
7.76
7.68
7.67
7.66
7.67
7.48
7.67
7.80
7.86
7.84
7.72
7.71
7.64
7.88
7.92
7.84
7.73
4 Н
8.30
9.55
9.39
8.74
8.75
8.75
7.74
8.77
8.80
8.98
9.24
9.23
9.21
9.19
9.24
9.49
9.44
8.79
6 Н
7.40
8.17
8.28
8.33
8.33
8.32
8.24
8.38
8.35
8.60
8.35
8.34
8.3
7 Н
7.06
7.22
7.12
7.18
7.18
7.19
7.17
7.20
7.26
7.38
7.16
7.17
7.17
7.12
7.15
7.28
7.29
a-Н
b-Н
ortho
meta
СН3
1
2
3
2.67
4
8.45
8.43
8.42
8.36
8.48
8.47
8.69
7.73
7.76
7.64
7.58
7.77
7.86
8.03
8.39
8.46
7.98
7.93
7.94
7.90
7.95
7.93
8.14
7.66
7.63
7.64
7.42
7.65
7.65
7.74
8.08
8.00
8.13
8.08
8.19
8.07
8.21
8.12
7.58**
7.36
7.08
6.77
7.64
7.75
8.57
7.44**
7.25
7.00
6.72
7.49
7.64
8.11
7.38
7.39
5
2.39
3.84
2.99
6
7
8
9
10
11
12
13
14
15
16
17
18
19
7.71
7.73
7.80
7.63
7.70
7.79
8.26
8.15
8.10
2.34
3.80
2.97
8.18
8.36
8.44
8.50
8.65
2.40
2.40
* Spin-spin coupling constants (Hz): 2H 1.2-1.8 and 3.7-4.3; 3H 3.7-4.3 and 8.5-8.8; 4H 1.2-1.5 and 7.3-8.9;
6H 7.9-8.6; 7H 7.0-8.6; αH 14.7-15.9; βH 15.3-15.9; ortho 5.3-8.6; meta 6.1-9.2
** Overlapped signals of para and meta protons
Table 4. Antifungal activity for conventional fungi. Data are the minimal concentrations to inhibit fungi growth/minimal fungicide concentrations, in μg/mL.
№
Ca
Ct
Sc
Cn
Afl
Afu
An
Mg
Tr
Tm
125/
>250
250/
>250
125/
>250
31.2/
>250
125/
>250
125/
>250
125/
>250
125/
250
62.5/
125
62.5/
125
5
125/
>250
250/
>250
125/
>250
125/
>250
250/
>250
250/
>250
250/
>250
125/
250
125/
250
125/
250
12
14
62.5/
>250
125/
>250
62.5/
>250
62.5/
>250
125/
>250
125/
>250
125/
>250
62.5/
62.5
62.5/
125
62.5/
125
Ca: Candida albicans; Ct: Candida tropicalis; Sc: Saccharomyces cerevisiae; Cn: Cryptococcus neoformans; Afl: Aspergillus flavus; Afu: Aspergillus
fumigatus; An: Aspergillus niger; Mg: Microsporum gypseum; Tr: Trichophyton rubrum; Tm: Trichophyton mentagrophytes.
CONCLUSIONS
ACKNOWLEDGEMENTS
Nine new chalcones were synthesized and their melting temperatures
were obtained; their structures were demonstrated by IR, NMR and elemental
analysis.
The authors want to thank Dr. Susana Zacchino in the Facultad de Ciencias
Bioquímicas y Farmacéuticas of the Universidad Nacional de Rosario,
Suipacha, Argentina and Dr. Jairo Quiroga in the Universidad del Valle,
Colombia for the experiments on biological activity.
1.
These chalcones showed trans configuration and strong
intramolecular hydrogen bonds; these intramolecular bonds were demonstrated
for 1-4 and 11; the hydrogen bonds remained in proton-donor solutions of
phenol and acetic acid and were broken only in trifluoroacetic acid solutions.
These chalcones have a strong potential as chelating agents in analytical
chemistry.
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The bromination of these chalcones occurred on the quinoline
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The chalcones showed an important antifungal activity.
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J. Chil. Chem. Soc., 57, Nº 3 (2012)
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