COPPER(II) IONS MEDIATED CRYSTAL FORMATION OF 3-(3-HYDROXY PHENYL)-1-PHENYL-1H-PYRAZOLE-4-CARBALDEHYDE

Schiff base obtained from 3-hydroxyacetophenone and phenylhydrazine was subjected to Vilsmeier-Haack reaction to obtain 3-(3-hydroxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (2). Successful formation of crystals of 2 was achieved using copper ions (Cu) as template. Present paper reports study of spectroscopic characterization and single-crystal X-ray study of 2. Hydrogen bonding network between 2 and water molecules enable the formation of 2D layer along ab-plane supported also by π···π stacking interactions of parallel molecules in head-to-head fashion.


INTRODUCTION
Vilsmeier-Haack reaction allows the formylation of electron-rich arenes. Classical Vilsmeier-Haack reaction [1][2][3] involves electrophilic substitution of a suitable carbon nucleophile with a chloromethyleneiminium salt. Hydrolysis of iminium salt affords aldehyde derivative and this transformation (Ar-H→Ar-CHO) is the most widely studied outcome of this protocol. This reaction has a broad application as iminium salt can be converted to compounds with various functional groups based on the reagent used in later step. For example, the intermediate iminium salt can be converted to nitrile derivative (Ar-CN) by treatment with hydroxylamine [4].
It is also one of the well-established reactions for the synthesis of pyrazole-4-carbaldehyde compounds where hydrolysis of iminium salt gives the final product. Pyrazole is also an important scaffold in many natural products. Pyrazole containing compounds are usually associated with activities such as antifungal [5], anti-inflammatory [6], insecticidal [7] and antiviral [8] properties. Substituted pyrazoles showed selective anti-proliferative actions on many human cancer cells and hold promise as inhibitors of cellular proliferation [9][10][11][12][13]. Anticancer activity of Schiff bases of pyrazole-4-carbaldehyde derivatives are also reported [14].

Material and method
All the starting materials and solvents were purchased from commercial sources and were used without further purification. Microwave oven of Samsung, 800W output with digital timer and clock was used for synthesis. Melting points were determined in open capillaries using Electro thermal melting point apparatus and are uncorrected. Progress of reactions was monitored by TLC. Infrared (IR) spectra (4000-600 cm -1 ) of the samples were recorded using a Perkin-Elmer Spectrum 100, equipped with a Specac Golden Gate Diamond ATR as a solid sample support. 1 H NMR spectra were recorded with a Bruker Avance III 500 NMR spectrometer with TMS as 590 internal reference. MS spectra were recorded with an Agilent 6624 Accurate Mass TOF LC/MS instrument (ESI ionization). Elemental (C, H, N) analyses were obtained using Perkin-Elmer 2400 Series II CHNS/O Elemental Analyzer.
Synthesis of 1-phenyl-3-hydroxy-1H-pyrazole-4-carbaldehyde (2) Compound was synthesized as reported in literature [15]. A mixture of 3-hydroxyacetophenone (1.36 g, 10.0 mmol), phenylhydrazine (1.08 g, 10.0 mmol), 1 drop of conc. HCl was prepared in a 100 mL conical flask. Ethanol (5 mL) was added as microwave active energy dissipater solvent and the reaction mixture was subjected to microwave irradiation of 20 s at 450 W. The microwave irradiation was carried out in batches of 5 s each for a period of 2 min. The resultant dry solid 1 was dissolved in excess of DMF in an ice bath followed by addition of POCl 3 (15 mmol, 2.30 g) with continuous stirring at cold conditions maintaining temperature at about 8 to 10 °C. The reaction mixture was allowed to attain room temperature and heated at about 80 °C for 1 h in a 150 mL beaker. The reaction mixture, upon hydrolysis by distilled water, gave off white colored solid. The solid obtained was washed with water to remove excess of HCl, filtered and dried. It was recrystallized with ethanol to obtain pure compound 2 as sticky mass. Yield

Crystal growth of 2
Compound 2 was obtained as sticky mass even after repeated attempts for crystal growth in ethanol or chloroform. 2 is insoluble in aqueous ethanol. However, it is soluble when 10 mL of 0.1 M solution of copper sulfate was added to 30 mL solution of 2 in 70% ethanol. This solution was heated for 5 to 10 min to obtain a clear solution. It was allowed to cool to room temperature and filtered. The filtrate was kept overnight in dark chamber without disturbance to obtain fine crystals of 2.
IR spectra of the compound shows stretching band at 3129 cm -1 for the phenolic -OH group. Stretching band for C-H proton of aldehyde group is observed at 2887 cm -1 and the carbonyl stretching frequency for aldehyde group is observed at 1661 cm -1 . The C=N, C-N and N-N stretching frequencies for the bonds in pyrazole ring are observed at 1597 cm -1 , 1508 cm -1 and 1215 cm -1 , respectively. 1 H NMR spectra of the compound recorded at 500 MHz in CDCl 3 showed singlet at δ 6.90 for one proton of C-H of aromatic ring adjacent to phenolic -OH. Peaks from the range of δ 7.29-7.36 are an overlap of one triplet of proton and a doublet for two protons of the aryl C-H protons from phenolic ring. Two aromatic protons from the other phenyl ring shows doublet in the range of δ 7.98. The peak at δ 7.58 can be attributed to two aromatic protons of the phenyl ring. The proton at the para position of the phenyl ring is observed at δ 7.43. A singlet is observed at δ 9.29 for pyrazolic CH, singlet at δ 9.65 is observed for NH of the pyrazole ring and the singlet for one proton of aldehyde group is observed at δ 9.98.

X-ray crystallographic study
Single-crystal X-ray diffraction data were collected on an Agilent Technologies SuperNova Dual diffractometer with an Atlas detector using monochromated Mo-Kα radiation (λ = 0.71073 Å) at room temperature. The data were processed using CrysAlis Pro [16]. Structure was solved by direct methods using SHELXT2014 [17] and refined on F 2 using full-matrix least-squares procedures using SHELXL2017 [18] integrated in Olex2 [19]. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were readily located in a difference Fourier maps and were subsequently treated as riding atoms in geometrically idealized positions, with C-H = 0.93 Å and U iso (H) = 1.2U eq (C). Hydrogen atoms in water molecule and hydroxy group have been located by difference Fourier maps and refined restraining the bond lengths and with U iso (H) = 1.5U eq (O). CCDC 1899454 contains the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre. Crystallographic data are listed in Table 1. ]/(n/p)} 1/2 where n is the number of reflections and p is the total number of parameters refined.

RESULTS AND DISCUSSION
Titled compound 2 was obtained in two-step procedure (Scheme 1). From the starting material 3-hydroxyacetophenone and phenylhydrazine a Schiff base formed under microwave conditions and further transformed via Vilsmeier-Haack reaction using POCl 3 to obtain 3-(3-hydroxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (2). Compound 2 was obtained as sticky mass even after repeated recrystallizations. Attempts to obtain crystals of 2 suitable for XRD analysis by employing evaporation method at room temperature using common organic solvents like methanol, ethanol and chloroform or various combinations of solvents were not successful. However, successful formation of crystals of 2 was achieved by metal assisted method using copper sulfate as template. Usually such reactions lead to formation of a coordination complex of ML 2 type if ligand geometry is favorable for formation of five or six membered ring. In this case, there is no formation of coordination complex like ML 2 type. Instead, the metal ion (Cu 2+ ) only helps in formation of hydrated crystal of the compound (2).
Hydrogen bonding O1-H1···O3 between hydroxy group of 2 as a hydrogen bond donor and the water molecule as hydrogen bond acceptor and a O3-H3A···O1 between the water molecule as hydrogen bond donor and hydroxy group of 2 as a hydrogen bond acceptor enables the formation of a R 4 4 (8) graph set motif [31] connecting two 2 molecules and two water molecules (Table 2). Furthermore, water molecule forms as a hydrogen bond donor O3-H3B···O2 interaction with the adjacent 2 molecule forming R 2 2 (7) graph set motif in cooperation with C3-H3···O3 interaction. R 3 3 (12) graph set motif is also present due to the C16-H16···O2 hydrogen bonding between formyl groups of two adjacent 2 molecules and the hydrogen bonds formed by water molecule as hydrogen bond donor ( Figure 2, Table 2). These hydrogen bonding enable the formation of layer along ab-plane supported also by π···π stacking interactions of parallel molecules in head-to-head fashion with centroid-to-centroid distance of 3.880(2) Å and ring slippages of 1.627 Å between pyrazole rings, 1.645 Å between phenyl rings, and 1.694 Å between phenolic rings (Figure 2).  1 -x, -½ + y, ½ -z

CONCLUSION
The formation of Schiff base from 3-hydroxyacetophenone and phenyl hydrazine and further transformation by Vilsmeier-Haack reaction gave 3-(3-hydroxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (2). Successful formation of crystals of 2 was achieved by metal assisted method using copper sulphate as template. In the crystal structure hydrogen bonding network between 2 and water molecules enable the formation of 2D layer along ab-plane supported also by π···π stacking interactions of parallel molecules in head-to-head fashion.