Synthesis, Characterization and Molecular Mechanics Potential Energy Evaluation of 4-amino-2, 3-dimethyl-1-phenyl-3-pyrazolin-5-one ligand and its transition metal complexes

I.E. Otuokere¹*, C.O. Alisa² and P. Nwachukwu¹

¹Department of Chemistry, Michael Okpara University of Agriculture, Umudike

²Department of Chemistry, Federal University of Technology, Owerri.

*Corresponding Author E-mail: ifeanyiotuokere@gmail.com

ABSTRACT:

4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one is a metabolite of aminopyrine with analgesic, anti-inflammatory, and antipyretic properties. Cd(II), Co(II), Cu(I), Ni(II), Pt(II) and Zn(II) complexes of 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one have been synthesized. The ligand and complexes were characterized based on electronic, infrared, ¹H NMR and ¹³C NMR spectroscopy. Spectroscopic investigation revealed that the ligand coordinated to the metal ions through the carbonyl and amino functional groups. 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one behaved as a bidentate ligand. Five membered ring chelates complexes were formed. Molecular mechanics potential energy evaluation showed that the most feasible position for 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one and its complexes to exhibit analgesic, anti-inflammatory and antipyretic activity was found to be in the range 56.75143626 - 82.65547188 kcal/mol.

KEYWORDS: 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one, complexes, energy, spectra, ligand

INTRODUCTION:

Pyrazolone, a five-membered-ring lactam, is a derivative of pyrazole that has an additional keto (C=O) group. It has a molecular formula of C₃H₄N₂O. There are two possible isomers: 3-pyrazolone and 5-pyrazolone.^[1] Derivatives of 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one received much attention due ton their analytical, clinical, analgesic, antispasmodic, antipyretic and pharmacological potentials.^[1] 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one is a metabolite of aminopyrine with analgesic, anti-inflammatory, and antipyretic properties. Due to the risk of agranulocytosis its use as a drug is discouraged ^[1]. It is used as a reagent for biochemical reactions producing peroxides or phenols. Ampyrone stimulates liver microsomes and is also used to measure extracellular water ^[1] .

Pyrazolone was first prepared by Knorr in1883 when he was trying to synthesis quinoline derivatives, but he obtained pyrazolone derivative called antipyrin, also called phenazone^[2]. When pyrazolones were discovered, they were only known as non-steroidal anti-inflammatory agents (or drugs) – NSAID, but in recent times, they are known to exhibit antioxidant, anticancer, antibacterial and several other pharmacological actions ^[2-4]. Pyrazolone derivatives are important class of heterocyclic compounds that occur in many drugs and synthetic products^[5]. These compounds exhibit remarkable antitubercular^[6,7], antifungal^[8,9], antibacterial^[10], anti-inflammatory^[11], and antitumor activities^[12]. An efficient one-pot method to generate structurally diverse and medicinally interesting pyrazolone derivatives in good to excellent yields of 51–98% under microwave irradiation and solvent-free conditions have been developed ^[13]. This development of a one-pot reaction using readily available chemicals was considerable significance due to its synthetic efficiency and atom economy. The geometry of Ba(II), Sr(II) and Zn(II) with 1-phenyl-3-methyl-4- (p-nitrobenzoyl) pyrazolone-5(HNPz) have been reported^[14]. The study indicated the formation of octahedral complexes which were presumed to have been formed through the enolic and carbonyl oxygen atoms of the coordination reagent; in which water molecules completed the expected coordination numbers. Novel oxovanadium(IV) complexes with 4-acyl pyrazolone ligands showed catalytic activity towards the oxidation of benzylic alcohols ^[15]. Novel ruthenium half-sandwich complexes containing (N,O)-bound pyrazolone-based β-ketoamine ligands displayed moderate cytotoxicity toward the human ovarian cancer cell lines A2780 and A2780cisR, the latter line having acquired resistance to cisplatin ^[16]. Terbium complexes of pyrazolone derivatives have been reported to emit green fluorescence characteristic of terbium ions, possessed strong fluorescence intensity, and showed relatively high fluorescence quantum yields ^[17]. The structure of the 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one ligand is shown in Figure 1.

Based on the synthetic applications of pyrazolone derivatives, we hereby present the synthesis, characterization and molecular mechanics potential energy evaluation of 4-amino-2, 3-dimethyl-1-phenyl-3-pyrazolin-5-one ligand and its transition metal complexes.

Experimental:

All the chemical and solvents used were of analytical grade. Melting points were determined in open capillary tubes. UV-Visible spectra were carried out in DMSO using a Shimadzu UV-1601 spectrophotometer. Infrared spectra (cm^-1) were recorded on a Shimadzu-8400 FT-IR spectrometer using KBr disc. The ¹H NMR (600 MHz) and ¹³C NMR (150 MHz) spectra were recorded on a Brucker Avance III 600 NMR spectrometer using TMS as an internal standard (chemical shift in δ, ppm) and DMSO-d₆ as solvent.

Synthesis of the complexes:

2.03 g of 4-amino-2, 3-dimethyl-1-phenyl-3-pyrazolin-5-one was dissolved in 50 ml methanol. 2.28 g of CdCl₂. H₂O was also dissolved in 50 ml methanol. The two solutions were mixed together and refluxed for 4 hours. The product obtained was dried in a desiccators. The yield was recorded. The same procedure was carried out with 1.70 g CuCl₂.2H₂O; 2.37 g of CoCl₂.6H₂O; 1.36 g of ZnCl₂; 2.37 g of NiCl₂.6H₂O and 2.65 g of PtCl₂.

The structure of 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one and complexes was drawn in ACD Lab Chem Sketch software. Molecular mechanics (geometry optimization) was carried out using PM3 semi-empirical QM parameterization according to Hartree-Fock calculation method by Argus Lab 4.0.1 software [18]. Geometry of the molecule converged after the molecule was drawn and cleaned in Argus Lab. The program computed the potential energies. The energy (E) of the molecule was calculated as a sum of terms as in equation (1).

These terms are of importance for the accurate calculation of geometric properties of molecules. The set of energy functions and the corresponding parameters are called a force field [19].

RESULTS:

The Physical properties, Electronic spectral data, infrared spectral data, ¹HNMR chemical shifts data δ, (ppm), ¹³CNMR chemical shifts data (δ, ppm) and molecular mechanics potential energy evaluation are presented in Tables 1, 2, 3, 4, 5 and 6 respectively.

Table 1: Physical properties of the ligand and complexes

Compound	Melting point (^oC)	Colour	Yield (%)	Solubility at 25^oC
				H2O	Ethanol	Hexane	Ether
C11H13N3O	105 - 110	Pale yellow	----	Sparingly soluble	soluble	insoluble	Sparingly soluble
[Cd(C11H13N3O)]	198 - 202	Brownish yellow	86.00	Sparingly soluble	Sparingly soluble	insoluble	insoluble
[Co(C11H13N3O)]	120 - 127	Dirty brown	54.43	Sparingly soluble	Sparingly soluble	insoluble	insoluble
[Cu(C11H13N3O)]	157 - 160	black	94.00	Sparingly soluble	Sparingly soluble	insoluble	insoluble
[Ni(C11H13N3O)]	220 - 226	Lemon green	54.24	Sparingly soluble	Sparingly soluble	insoluble	insoluble
[Pt(C11H13N3O)]	221 - 227	Dark green	55.00	Sparingly soluble	Sparingly soluble	insoluble	insoluble
[Zn(C11H13N3O)]	145 - 148	Dark yellow	92.90	Sparingly soluble	Sparingly soluble	insoluble	insoluble

Table 2: Electronic spectral data of ligand and complexes

Compound	Wavelength (nm)	Assignment
C11H13N3O	275, 322	ILCT
[Cd(C11H13N3O)]	279 380	ILCT LMCT
[Co(C11H13N3O)]	281 383 463 524	ILCT LMCT A2 → T2 A2 → T1(F)
[Cu(C11H13N3O)]	289 387 493	ILCT LMCT T2 → E
[Ni(C11H13N3O)]	292 393 453 564 603	ILCT LMCT T1(F) → T2 T1(F) → T1(P) T1(F) → A2
[Pt(C11H13N3O)]	267 376 488 553 614	ILCT LMCT T1(F) → T2 T1(F) → T1(P) T1(F) → A2
[Zn(C11H13N3O)]	328 388	ILCT LMCT

Table 3: Infrared spectra of ligand and complexes

Compound	ν(C=O) Stretch	ν (N-H) Stretch	ν (C-C) Aromatic stretch	ν (Ar-H) Aromatic stretch	ν (C-H) stretch Alkanes	ν (C-N) stretch	M-O stretch	M-N stretch
C11H13N3O	1650.00	3434.28	1490.41	3040.00	2908.57	1119.43	Absent	Absent
[Cd(C11H13N3O)]	1632.48	3320.66	1491.28	3080.09	2908.57	1110.88	404.04	495.33
[Co(C11H13N3O)]	1613.41	3420.87	1494.23	3080.65	2906.99	1110.88	404.97	482.21
[Cu(C11H13N3O)]	1639.73	3197.00	1495.00	3047.56	2912.83	1125.12	402.13	498.18
[Ni(C11H13N3O)]	1633.00	3314.66	1499.32	3018.99	2912.44	1113.88	409.15	484.23
[Pt(C11H13N3O)]	1619.47	3314.66	1491.19	3060.50	2914.55	1113.73	361.39	441.19
[Zn(C11H13N3O)]	1620.78	3227.30	1495.65	3076.98	2914.60	1110.80	355.69	441.19

Table 4: ¹HNMR chemical shifts data of ligand and complexes (ppm)

Compound	Ar protons 7,11	Ar protons 8, 10	Ar protons 9	NH2 protons 14	CH3 protons 13	CH3 protons 12
C11H13N3O	7.77	7.38	7.17	6.86	2.12	3.08
[Cd(C11H13N3O)]	7.74	7.39	7.16	4.13	2.17	3.10
[Co(C11H13N3O)]	7.78	7.42	7.15	4.19	2.14	3.09
Cu(C11H13N3O)]	7.75	7.36	7.19	4.16	2.16	3.13
[Ni(C11H13N3O)]	7.79	7.41	7.17	4.21	2.13	3.14
[Pt(C11H13N3O)]	7.77	7.37	7.11	4.17	2.17	3.09
[Zn(C11H13N3O)]	7.71	7.35	7.14	4.22	2.10	3.13

Table 5: ¹³CNMR chemical shifts data of ligand and complexes (ppm)

Compound	C=O 5	Ar C 7, 11	Ar C 9	Ar C 8, 10	Ar C 6	CH3 13	CH3 12	C=C 3	C=C 4
C11H13N3O	163.09	126.19	128.14	129.44	134.12	11.96	32.11	138.03	145.05
[Cd(C11H13N3O)]	182.77	125.31	127.75	129.39	134.38	11.99	33.82	138.06	144.61
[Co(C11H13N3O)]	182.70	125.30	127.72	129.34	134.30	11.94	33.85	138.05	145.60
Cu(C11H13N3O)]	182.27	125.30	127.70	129.32	134.33	11.95	33.88	138.08	143.69
[Ni(C11H13N3O)]	181.77	125.91	127.15	129.79	134.18	11.29	33.87	138.96	145.11
[Pt(C11H13N3O)]	182.37	125.91	127.45	129.59	134.48	11.49	33.22	138.46	145.21
[Zn(C11H13N3O)]	182.71	125.38	127.77	129.31	134.32	11.93	33.84	138.09	145.51

DISSCUSION:

The ligand and complexes are stable, non- hygroscopic, exhibited high melting points and are sparingly soluble in polar solvents (Table 1).

Electronic spectra:

The electronic spectral data (Table 2) of the ligand showed absorption bands at 275 and 322 nm. These bands have been assigned n → π* and π → π* intraligand charge transfer transition (ILCT). The spectrum of cadmium complex showed two absorption bands. These bands were interpreted to be intraligand charge transfer (ILCT) and ligand to metal charge transfer (LMCT) transition respectively. The absorption bands in the cobalt complex were assigned intraligand charge transfer (ILCT), ligand to metal charge transfer (LMCT), A₂ → T₂ and A₂ → T₁(F) transitions respectively.

Table 6: Molecular Mechanics Potential Energy Evaluation

Energy Com-ponents	C11H13N3O	[Cd(C11H13N3O)]	[Co(C11H13N3O)]	Cu(C11H13N3O)]	[Ni(C11H13N3O)]	[Pt(C11H13N3O)]	[Zn(C11H13N3O)]
MM Bond	0.00218028	0.00263820	0.00440238	0.00256046	0.00584114	0.00356877	0.00266616
MM Angle	0.06778804	0.10035311	0.09570203	0.10351435	0.10065136	0.09621015	0.10104102
MM Dihedral	-0.00000000	0.00639623	0.00002363	0.00639626	0.00003039	0.00002594	0.00639376
MM ImpTor	0.00000000	0.00000325	0.00000504	0.00000360	0.00000732	0.00000551	0.00000314
MM vdW	0.02047077	0.01924232	0.01845469	0.01924509	0.01816001	0.01847518	0.01882888
MM Coulomb	0.00000000	0.00000000	0.00000000	0.00000000	0.00000000	0.00000000	0.00000000
Total (a.u.)	0.09043909	0.12863311	0.11858778	0.13171976	0.12469022	0.11828555	0.12893296
Total (kcal/mol)	56.75143626	80.71857078	74.41501972	82.65547188	78.24436632	74.22537270	80.90672729

The appearance of three peaks in the copper complex spectrum suggested intraligand charge transfer (ILCT), ligand to metal charge transfer (LMCT) and T₂ → E transitions. The spectra of nickel and platinum complexes showed five absorption bands. These five absorption bands have been assigned intraligand charge transfer (ILCT), ligand to metal charge transfer (LMCT), T₁(F) → T_{2 ,} T₁(F) → T₁(P) and T₁(F) → A₂ transitions respectively. The two bands in the spectrum of zinc complex were proposed to be intraligand charge transfer (ILCT) and ligand to metal charge transfer (LMCT) transitions respectively.

Infrared spectra:

The infrared spectral data (Table 3) of the ligand showed a peak at 1650 cm^-1 which corresponded to ν(C=O) Stretch of RCONR₂ (amides). In the spectra of the metal complexes this peak shifted to lower vibration frequencies (1613.41 - 1639.73 cm-¹). This shift suggested the involvement of C=O oxygen lone pair in coordination. The coordination of metal ion to C=O caused a weakening of the C=O bond, the electron density was increased and consequently the decrease in vibration frequency to a lower wave number. The vibration frequency 3434.28 cm-¹ in the spectrum of the ligand was assigned ν(N-H) Stretch. This vibration frequency was shifted to 3197.00 - 3320.66 cm-¹ in the spectra of the complexes. This shift suggested the involvement of nitrogen lone pair of NH₂ in coordination. The coordination of metal ion to NH₂ caused a weakening of the N-H bond, the electron density was increased and consequently the decrease in vibration frequency to a lower wave number. The appearance of new peaks at 355.69 - 409.15cm-¹ and 441.19 - 498.18 cm-¹ in the spectra of the complexes suggested M-O and M-N bonds ^[20].

¹H NMR:

The NMR spectra of the ligand and complexes (Table 4) showed aromatic protons chemical shift at 7.11 – 7.79 ppm. The methyl protons chemical shift appeared at 2.10 -3.14 ppm. In the spectrum of the ligand, the chemical shift of the NH₂ protons appeared at 6.86 ppm. This NH₂ signal of the complexes shifted upfield (4.13 – 4.22 ppm). This shift suggested the involvement of nitrogen lone pair of NH₂ in bonding.

¹³C NMR:

The spectra of the ligand and complexes (Table 5) showed the chemical shift positions of aromatic carbons, methyl carbons and methylene carbons at 125.30- 134.48, 11.29 - 33.88 and 138.03 – 145.60 ppm repectively. In the spectrum of ligand, the chemical shift position of carbonyl (C=O) appeared at 163.09 ppm. This C=O chemical shift was shifted downfield (182.27- 182.77 ppm) in the spectra of the complexes. This shift also suggested the involvement of oxygen lone pair of carbonyl in complexation. Molecular mechanics potential energy evaluation (Table 6) showed that the most feasible position for 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one and its complexes to exhibit analgesic, anti-inflammatory, and antipyretic activity was found to be in the range 56.75143626 - 82.65547188 kcal/mol Based on the spectroscopic characterization, the following structures (Figure 2) have been proposed for the complexes.

Figure 2: Suggested structures for 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one metal complexes

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Received on 17.03.2015 Modified on 25.03.2015

Accepted on 11.04.2015 ©A&V Publications All right reserved

Res. J. Pharm. Dosage Form. & Tech. 7(2): April-June, 2015; Page 129-133

DOI: 10.5958/0975-4377.2015.00019.1