Journal of Chemical Science
Journal of Chemical Science
Journal of Chemical Science
REGULAR ARTICLE
Abstract. The present research work deals with the green synthesis of substituted pyrazolone derivatives
4(a–f) from 2,4-dinitrophenylhydrazine with various substituted aromatic aldehyde and ethyl acetoacetate in
the presence of silica-supported zinc chloride (SiO2/ZnCl2) as a recyclable Lewis acid catalyst. The syn-
thesized compounds were structurally characterized with IR, 1H NMR, Mass spectra and elemental analysis.
All these compounds were tested for their antioxidant activity by using the DPPH radical scavenging method.
Keywords. Pyrazolone; silica-supported zinc chloride catalyst; green synthesis; anti-oxidant activity.
*For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1679-5) contains supple-
mentary material, which is available to authorized users.
105 Page 2 of 7 J. Chem. Sci. (2019) 131:105
pyrazolone derivatives through a condensation reaction. analysis (CHN) and melting points. IR spectra (KBr
In recent years, a few catalysts have been comprised as pellet) were recorded on Bruker Tensor 27 FT-IR
3-aminopropylated silica gel,15 silica sulphuric acid,16 spectrometer at Sri Venkateswara College of Pharmacy,
N-(3-silicapropyl)-N-methyl imidazolium hydrogen Chittoor. 1H NMR spectra were recorded on a Bruker
sulphate,17 sodium dodecyl sulphate,18 xanthan sulfuric DRX400 spectrometer and the elemental analysis was
acid,19 1,3-disulfonicacid imidazolium tetrachloroalu- performed using a Heraeus CHN-O-Rapid analyzer at
minate,20 silica-bonded N-propylpiperazine sulfamic Sophisticated Instrumentation Facility, VIT University,
acid,21 as reusable solid catalysts. Almost all these Vellore. NMR spectra were recorded in CDCl3 and
methods had several limitations such as more reaction DMSO-d6. Chemical shifts (d) are reported in ppm
times, less percentage yields, tiresome work-up proce- relative to tetramethylsilane (TMS) as an internal
dures, usage of various toxic solvents and catalysts. standard. J values are given in Hz. High-resolution
Therefore, it is needed to overcome these difficulties and mass spectrometry (HRMS) spectra were recorded on a
develop a new way for the synthesis of pyrazolone JEOL TMS-HX 110 mass spectrometer.
derivatives.
Free radicals play a vital role in human cell pro-
tection as immortality development and breakthrough 2.2 Synthesis
of diseases. Free radicals also called as reactive oxy-
In this present work, compounds were synthesized
gen species (ROS), which contain hydroxyl radicals
as shown in Figure 2. Substituted 4-benzylidene-3-
(OH-), superoxide anions (O2-), nitric oxide (NO-),
methyl-1-(2,4-dinitrophenyl)-1H-pyrazol-5(4H)-one
hydrogen peroxide (H2O2) and lipid peroxidation. As
were prepared by condensation of substituted ben-
antioxidants can act as a defence mechanism against
zaldehyde, ethyl acetoacetate and 2,4-dinitro-
exposure to free damage cells further decisive during
phenylhydrazine in presence of silica-supported
the air pollution, smoke of tobacco, alcohols, pesti-
zinc chloride (SiO2/ZnCl2) as a recyclable catalyst
cides, drug addiction, fried groceries, and many more
by multicomponent reaction (MCR). Substituted
can enhance the radical exposure.22
pyrazolone was prepared by the reported proce-
The present work focused on developing efficient
dure. The most important target was to develop an
and green methods for the synthesis of pharmacolog-
effective multi-component approach for the syn-
ically active heterocyclic compounds. Nowadays,
thesis of substituted 4-benzylidene-3-methyl-1-
multi-component reactions (MCRs) play a vital role in
(2,4-dinitrophenyl)-1H-pyrazol-5(4H)-one [4]
the improvement of cost-effective and eco-friendly
through the reaction of various substituted aromatic
protocols in organic synthesis in a single-step reaction.
aldehyde [1] with 2,4-dinitrophenylhydrazine [2]
In persistence of interest in the synthesis of hetero-
and ethyl acetoacetate [3] by using silica-supported
cyclic compounds, consequently, the synthesis of
zinc chloride (SiO2/ZnCl2) as a recyclable Lewis
pyrazolone moiety was performed by using a hetero-
acid catalyst. All the reactions were carried out by
geneous catalyst in water/ethanol, including their
refluxing with water/ethanol and the yield of the
spectroscopy data, and statistical analysis of their
obtained products 4(a–f) were generated in good to
antioxidant potential.
CH3
CH3
2. Experimental O
N CH
3
H3C
N
CH3
N
N
CH3
2.1 Materials and physical measurements O
All the chemicals and reagents used were obtained from Antipyrine Propyphenazone
Avra, Merck and Sigma-Aldrich Co. and were used
without additional purification. Melting points were H3C CH3 O
determined in open capillaries in Elico melting point O N N
O
apparatus and were uncorrected. The reactions were HO S N N N
O S
monitored by thin layer chromatography (TLC) using H3C O O
NO2 R NO2
NHNH2 O
CHO SiO2/ZnCl2
O O
R
Catalyst N
O2N H3C OC2H5 N NO2
C2H5OH/ H2O, H
60 oC
H3C
1 2 3 4(a-f)
4a H3CO 4d Cl
H3CO
H3C
N
4b 4e
H3C H3C N
CH3
4c 4f
OCH3 NO2
excellent yields ranged within 86–94% and results water (5 mL) the resulting mixture was extracted
are summarized in Table S1, Supplementary with ethyl acetate (3910 mL). The combined
Information. As mentioned in Table S1, different organic layers were washed with 10% NaHCO3 and
aryl aldehydes having electron-withdrawing and water, dried over anhydrous Na2SO4 and evaporated
electron-donating groups were found to give under reduced pressure. The resulting crude product
favourable compounds in good yields. substituted 4-benzylidene-3-methyl-1-(2,4-dinitro-phe-
nyl)-1H-pyrazol-5(4H)-one derivatives were purified by
recrystallization from hot ethanol to give the desired
2.3 Preparation of catalyst (SiO2/ZnCl2) products.
The catalyst ZnCl2 supported on silica gel was pre-
pared according to the previous procedure. About 2.7
g of ZnCl2 (12 mmol) was added to 9.1 g silica gel 2.5 Reusability of catalyst
(grade 60, 230–400 mesh) in 50 mL ethanol. The
reaction mixture was stirred and refluxed for 1 h in the The reusability of the catalyst was tested in the syn-
absence of light, filtered, washed with dry CCl4 and thesis of 4-benzylidene-3-methyl-1-(2,4-dinitro-phe-
dried under vacuum at 160 °C for 10 h.23 nyl)-1H-pyrazol-5(4H)-one. In a typical experiment,
after completion of the reaction, (SiO2/ZnCl2) was
isolated from the reaction mixture by filtration and
2.4 Synthesis of substituted 4-benzylidene-3- washed with ethyl acetate and dried over anhydrous
methyl-1-(2,4-dinitrophenyl)-1H-pyrazol-5(4H)- Na2SO4. If ZnCl2 is used as a catalyst, it leaches the
one using SiO2/ZnCl2 catalyst Zn2? into the reaction. To minimize the leaching of
zinc ions, SiO2 was used as a supporting agent to bind
An equimolar mixture of substituted aromatic alde- the zinc ions. However, no significant leaching of the
hyde (0.02 mol), ethyl acetoacetate (0.02 mol) and 2,4- modifier was observed under our reaction conditions.
dinitrophenylhydrazine (0.02 mol) were added to 0.10 In the reaction mixture, Zn content was verified by
g of supported ZnCl2 on SiO2 (15%, w/w) in 10 mL of analysing after filtering-off the catalyst. Moreover, no
water (or) ethanol in round bottom flask equipped with reaction was observed in the solvent after removing
condenser at 60 °C for the given time (Table S1, the catalyst. Using the recycled catalyst for consecu-
Supplementary Information). After completion of the tive times in the chemical reaction of benzaldehyde
reaction (monitored by TLC), and diluted with cold and 2,4-dinitrophenyl-hydrazine furnished the product
105 Page 4 of 7 J. Chem. Sci. (2019) 131:105
with no significant decrease in the reaction yield. The (KBr, cm-1): 1422 (C=Caromatic), 1694 (C=O), 1332 (NO2);
1
recovered catalyst (98%) was reused three times H NMR (400 MHz, CDCl3, d, ppm): 8.40–9.73 (m, 3H,
without any loss of activity. This reusability demon- phenyl ring), 7.26 (s, 1H, -C=H), 6.71–7.74 (m, 4H, phenyl
strates the high stability of the catalyst under the ring), 1.29 (s, 3H, -CH3), 3.44 (s, 6H, 2xN-CH3); Analytical
operating conditions. cal. C19H17N5O5: C, 57.72; H, 4.33; N, 17.71; Found: C,
57.65; H, 4.38; N, 17.67; MS (EI): (m/z) Calculated for
C19H17N5O5 [M?H]? : 395.1230; Found, 395.3688 (Rel.
2.6 Spectral data of synthesized compounds Int.100%).
2.6f Compound 4f: (4Z)-4-(2-nitrobenzylidene)-3-methyl-1-
2.6a Compound 4a: (4Z)-4-(3,4-dimethoxybenzylidene)-3-
(2,4-dinitrophenyl)-1H-pyrazol-5(4H)-one Light yellow
methyl-1-(2,4-dinitrophenyl)-1H-pyrazol-5(4H)-one Yel-
crystalline solid; Yield 88%; M.p. 212 °C; FT-IR (KBr,
low solid; Yield 92%; M.p. 218 °C23; FT-IR (KBr, cm-1): 1182,
cm-1): 1608 (C=Caromatic), 1725 (C=O), 1495, 1331 (NO2);
1412 (C=Caromatic), 1519 (C=N), 1695 (C=O), 1342 (NO2); 1H 1
H NMR (400 MHz, CDCl3, d, ppm): 8.41–9.10 (m, 3H,
NMR (400 MHz, CDCl3, d, ppm): 8.01–9.03 (dd, 3H, phenyl
phenyl ring), 7.27 (s, 1H, -C=H), 7.44–7.66 (m, 4H, phenyl
ring), 6.95 (s, 1H, -C=H), 6.83–7.20 (dd, 3H, phenyl ring), 2.29
ring); Analytical cal. C17H11N5O7: C, 51.39; H, 2.79; N,
(s, 3H, -CH3), 3.87 (s, 6H, 2x-OCH3); Analytical cal.
17.63; Found: C, 51.30; H, 2.82; N, 17.58; MS (EI): (m/z)
C19H16N4O7: C, 55.34; H, 3.91; N, 13.59. Found: C, 55.31; H,
Calculated for C17H11N5O7 [M?H]?: 397.2985; Found,
3.93; N, 13.60; MS (EI): (m/z) Calculated for C19H16N4O7
397.0658 (Rel. Int.100%).
[M?H]? : 412.3529; Found, 412.0632 (Rel. Int.100%).
2.6b Compound 4b: (4Z)-4-(4-(dimethylamino)benzyli-
dene)-3-methyl-1-(2,4-dinitro-phenyl)-1H-pyrazol-5(4H)-
one Orange crystalline solid; Yield 94%; M.p. 236 °C23;
2.7 Evaluation of in-vitro antioxidant activity
FT-IR (KBr, cm-1): 1417 (C=Caromatic), 1628 (C=N), 1713
(C=O), 1306 (NO2); 1H NMR (400 MHz, CDCl3, d, ppm):
The activity of the synthesized compounds was quanti-
8.40–9.03 (dd, 4H, phenyl ring), 8.01 (d, 1H, -C=H), tatively measured by diphenylpicrylhydrazyl (DPPH)
6.80–6.83 (dd, 3H, phenyl ring), 2.94 (s, 3H, -CH3), 2.29 (s, radical assay method to characterize antioxidants.25
6H, 2xCH3); Analytical cal. C19H17N5O5: C, 57.72; H, 4.33; When antioxidants react with stable free radical (DPPH),
N, 17.71; Found: C, 57.68; H, 4.37; N, 17.65; MS (EI): (m/ it gets converted into 1,1-diphenyl-2-picryl hydrazine.
z) Calculated for C19H17N5O5 [M?H]? : 396.1263; Found, The stable free radical DPPH was measured by a decrease
396.1236 (Rel. Int.100%). in absorbance at k 540 nm, which is purple in colour.
2.6c Compound 4c: (4Z)-4-(2-methoxybenzylidene)-3- Ascorbic acid was used as the standard drug. The per cent
methyl-1-(2,4-dinitrophenyl)-1H-pyrazol-5(4H)-one Light scavenging activity was calculated by using the formula,
yellow crystalline solid; Yield 91%; M.p. 228 °C24; FT-IR Control Test
(KBr, cm-1): 1418 (C=Caromatic), 1701 (C=O), 1561 (C=N), Scavenging activity ð%Þ ¼ 100
1506, 1325 (NO2); 1H NMR (400 MHz, CDCl3, d, ppm): Control
8.21–9.03 (dd, 3H, phenyl ring), 8.03 (d, 1H, -C=H), DPPH method The stock solution was prepared by using
7.10–7.41 (dd, 4H, phenyl ring), 2.29 (d, 3H, -CH3), 3.84 (s, DPPH (10 mg) dissolved in 10 mL dimethylsulfoxide
3H, -OCH3); Analytical cal. C18H14N4O6: C, 56.55; H, (DMSO) and added at various concentrations in ethanolic
3.69; N, 14.65; Found: C, 56.68; H, 3.67; N, 14.60; MS solution (10 mL). Solutions of the test compounds in vari-
(EI): (m/z) Calculated for C18H14N4O6 [M?H]? : ous concentrations (125, 250, 500 lg/mL) as well as of
382.0913; Found, 382.1682 (Rel. Int.100%). ascorbic acid as reference standard was prepared in ethanol.
An aliquot of each of these solutions (1.0 mL) was taken in
2.6d Compound 4d: (4Z)-4-(4-chlorobenzylidene)-3-methyl-
different 10 mL volumetric flasks to which the DPPH stock
1-(2,4-dinitrophenyl)-1H-pyrazol-5(4H)-one Orange
solution (1.0 mL) was added and volume was made to 10
crystalline solid; Yield 86%; M.p. 178 °C; FT-IR (KBr,
mL. The plates were incubated at 37 °C for 20 min and the
cm-1): 1127, 1424 (C=Caromatic), 1741 (C=O), 1512 (C=N),
absorbance of each solution was measured at 540 nm and
1320 (NO2); 1H NMR (400 MHz, CDCl3, d, ppm):
performed in triplicate.26–28
8.03–9.03 (dd, 3H, phenyl ring), 8.10 (m, 1H, -C=H),
6.82–7.45 (m, 4H, phenyl ring), 2.29 (s, 3H, -CH3); Ana-
lytical cal. C17H11N4O5Cl: C, 52.79; H, 2.87; N, 14.49;
3. Results and Discussion
Found: C, 52.68; H, 2.82; N, 14.53; MS (EI): (m/z) Cal-
culated for C17H11ClN4O5 [M?H]? : 386.0418; Found,
3.1 Spectral data and interpretation
386.1746 (Rel. Int.100%).
of the compounds
2.6e Compound 4e: (4Z)-4-(3-(dimethylamino)benzylidene)-
3-methyl-1-(2,4-dinitro-phenyl)-1H-pyrazol-5(4H)-one The products were identified by IR, 1H NMR spec-
Orange crystalline solid; Yield 90%; M.p. 230 °C; FT-IR troscopy and elemental analysis. In 1H NMR spectrum
J. Chem. Sci. (2019) 131:105 Page 5 of 7 105
of 4(a–f) it revealed a multiplet for the two aromatic free conditions, where, initially a trace amount of
hydrogen’s range at d 8.41–9.79 ppm and d 6.69–7.74 product had formed (Table S2, entry 1, Supplementary
ppm. One singlet related to the ethylene hydrogen at d Information), signifying the need of a catalyst. To
7.12–7.38 ppm and one singlet related to three enhance the yield of the product and to optimize the
hydrogen’s of –CH3 group at d 1.22–1.29 ppm. reaction conditions, it was then studied in the presence
of different catalysts such as AlCl3, ZnCl2, FeCl3,
3.1a Characterization of Catalyst (SiO2/ZnCl2): The SiO2-Cl, SiO2/ZnCl2. Maximum yield (86%) was
FT-IR spectrum of the catalyst (SiO2/ZnCl2) is shown obtained when the reaction was carried out with
in Figure S1, Supplementary Information. The FT-IR 10 mol% of the SiO2/ZnCl2 catalyst.
spectrum of the catalytic system displayed a Our analysis revealed that the optimum amount of
symmetrical stretching band at 3434 cm-1 for SiO2/ZnCl2 was relative to the reactant. The catalyst
hydroxyl group and the band resonating at 1610 plays a crucial role in the reaction. The results are
cm-1 was attributed to the bending of adsorbed water. summarized in Table S2, Supplementary Information.
A band appeared at 1172 cm-1 and this can be The reaction improved with almost the same ease with
attributed to the bending of Si-O-Si antisymmetric aromatic and aliphatic aldehydes. Various functional
stretching vibrations and the band at 817 cm-1 was groups such as methoxy (OCH3), dimethylamino
also evidence of the symmetric stretching vibration of (N(CH3)2), chloro (Cl) and nitro (NO2) groups con-
the rocking mode of Si-O-Si. The O-H stretching band taining compounds were tolerated. However, there are
around 3434 cm-1 was also presented in the catalyst. no significant changes in the yield that were observed
Considering the FT-IR spectra of SiO2/ZnCl2, it was when more than one substitute was present in the
concluded that ZnCl2 was successfully coated with phenyl ring (Table S1, entry 1). Hence, electronic and
silica layer.29 steric factors played a negligible role in this protocol.
H3C H3C
NO2
H O OH
N N N
NH 2 O O N N
1 3 NO2
NO2
Ar H H
SiO2
H3C Zn H3C
H Ar
O 2
H3C Ar
N N
N OH O
N
N
O 2N N O O2N
O2N
-H2O
Zn
NO 2 Zn NO2
SiO2
NO 2 4(a-f)
SiO2
17. Baghernejad M and Niknam K 2012 Synthesis of 4,40 - using ZnCl2/SiO2 as a recyclable heterogeneous cata-
(arylmethylene)bis(1h-pyrazol-5-ols) using silica-bonded lyst J. Mol. Catal. A: Chem. 337 52
ionic liquid as recyclable catalyst Int. J. Chem. 4 52 24. Prajapati S P, Patel D P and Patel P S 2012 Synthesis
18. Wang W, Wang S X, Qin X Y and Li J T 2005 and characterization of 6-amino-4-(substituted phenyl)-
Reaction of aldehydes and pyrazolones in the presence 1-(2,4-dinitrophenyl)-3-methyl-pyrazolo[3,4-b]pyr-
of sodium dodecyl sulfate in aqueous media Synth. idine-5-carbonitrile Elixir Org. Chem. 48 9414
Commun. 35 1263 25. Gupta A K, Kalpana S and Malik J K 2012 Synthesis
19. Kuarm B S and Rajitha B 2012 Xanthan sulfuric acid: An and in vitro antioxidant activity of new 3-substituted-2-
efficient, biosupported, and recyclable solid acid catalyst oxindole derivatives Indian J. Pharma. Sci. 74 481
for the synthesis of 4,40 -(arylmethylene)bis(1H-pyrazol- 26. Sreejayan N and Rao MNA 1996 Free radical scav-
5-ols) Synth. Commun. 42 2382 enging activity by curcuminoids Drug Res. 46 169
20. Khazaei A, Zolfigol M A, Moosavi Zare A R, Asgari 27. Mahesh B, Mohan G, Santhisudha S, Sridevi C,
Z, Shekouhy M, Zare A and Hasaninejad A 2012 Vasudeva R N, Vijaya T and Suresh R C 2017 Syn-
Preparation of 4,4’-(arylmethylene)-bis(3-methyl-1- thesis and antioxidant activity of some new N-alkylated
phenyl-1H-pyrazol-5-ol)s over 1,3-disulfonic acid pyrazole-containing benzimidazole Chem. Heterocycl.
imidazolium tetrachloroaluminate as a novel cata- Comp. 53 173
lyst RSC Adv. 2 8010 28. Anka P, Aleksandra M, Jovana J, Marko P, Danijela I K,
21. Tayebi S and Niknam K 2012 Synthesis of 4,40 -(aryl- Ivan D, Dragana S, Vladimir M and Jelena K 2018
methylene)bis(1H-pyrazol-5-ols) via multi-component Synthesis, characterization, antioxidant and antimi-
reactions by using silica-bonded sulfamic acid deriva- crobial activity of novel 5- arylidene-2-ferrocenyl-1,3-
tives Iran. J. Catal. 2 69 thiazolidin-4-ones J. Organometal. Chem. 869 1
22. Martins D M, Torres B G, Spohr P R, Machado P, 29. Wang S, Zhang Z, Liua B and Li J 2013 Silica coated
Bonacorso H G and Zanatta N 2008 Antioxidant potential magnetic Fe3O4 nanoparticles supported phospho-
of new pyrazoline derivatives to prevent oxidative dam- tungstic acid: a novel environmentally friendly catalyst
age Basic Clin. Pharmacol. Toxicol. 104 107 for the synthesis of 5-ethoxymethylfurfural from
23. Tamaddon F and Tavakoli F 2011 One-pot synthesis of 5-hydroxymethylfurfural and fructose Catal. Sci.
N-tert-butyl amides from alcohols, ethers and esters Technol. 3 2104
Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.
Alternative Proxies: