The interaction between K[PtCl3(Isopropyl eugenoxyacetate)] with pyridine’s derivatives

18 HNUE JOURNAL OF SCIENCE DOI: 10.18173/2354-1059.2017-0050 Chemical and Biological Science 2017, Vol. 62, Issue 10, pp. 18-25 This paper is available online at THE INTERACTION BETWEEN K[PtCl3(ISOPROPYL EUGENOXYACETATE)] WITH PYRIDINE’S DERIVATIVES Pham Van Thong 1 , Truong Thi Cam Mai 2 , Nguyen Thi Thanh Chi 1 1 Faculty of Chemistry, Hanoi National University of Education 2 Faculty of Chemistry, Quy Nhon University Abstract. The interactions of K[PtCl3( i PrEug)] (1) with either 2-aminopyridine (NH2Py) or 2-(aminomethyl)pyridine (NH2CH2Py) have been studied for the first time. The structures of obtained complexes, namely trans-[PtCl2( i PrEug)(NH2Py)] (2) and a mixture of [PtCl2(NH2CH2Py)] (3A) and trans-[PtCl2(NH2CH2Py)2] (3B), were determined by means of platinum analysis, EDX, IR, 1 H NMR spectroscopy. In 2, isopropyl eugenoxyacetate ( i PrEug) and 2-aminopyridine coordinate with Pt(II) through ethylenic double bond of the allyl group and N atom of the pyridine ring, respectively. 2-(aminomethyl)pyridine coordinates with Pt(II) via both N heterocyclic atom and NH2 group to form chelating complex (3A) but only coordinates with Pt(II) via N atom of the pyridine ring in 3B. Complex 2 exhibits high cytotoxic activity against KB cancer cell line with IC50 value of 10.5 μg/mL. Keywords: Pt(II) complexes, isopropyl eugenoxyacetate, pyridine derivatives, anticancer activity. 1. Introduction Since cisplatin was appointed as a chemotherapy drug for different types of cancer such as testicular or ovarian cancer, numerous Pt(II) complexes have been synthesized and examined for their antitumor activities [1, 2]. Beside the target of medical application, Pt and its complexes are known for essential roles in organic synthesis, especially many Pt-olefin complexes are important intermediates in transforming olefins into more valuable compounds [3, 4]. Recently, several Pt(II) complexes of the general formula K[PtCl3(olefin)] (olefin: safrole, eugenol or its derivatives) have been prepared [5-7]. The reactions of these complexes and different amines formed some series of Pt(II) complexes with the type of trans- [PtCl2(olefin)(amine)], some of which were tested and found to be potential inhibitory on several human cancer cell lines [7, 8]. However, the interaction between K[PtCl3(eugenol)] Received October 2, 2017. Revised November 23, 2017. Accepted November 30, 2017. Contact Nguyen Thi Thanh Chi, e-mail address: chintt@hnue.edu.vn The interaction between K[PtCl3(isopropyl eugenoxyacetate)] with pyridine’s derivatives 19 with some pyridine’s derivatives gave no trans-[PtCl2(eugenol)(amine)] but other unnormal products [9]. In this study, we report the interactions between K[PtCl3( i PrEug)] ( i PrEug: isopropyl eugenoxyacetate) with either 2-aminopyridine or 2- (aminomethyl)pyridine. 2. Content 2.1. Experimental 2.1.1. Interaction between K[PtCl3( i PrEug)] with some pyridine’s derivatives * Synthesis of starting complex (K[PtCl3( i PrEug)]) K[PtCl3( i PrEug)] (1) was synthesized by the reaction between Zeise’s salt and isopropyl eugenoxyacetate ester as follows: Isopropyl eugenoxyacetate (2.90 g, 11.0 mmol) was mixed with Zeise’s salt (3.86 g, 10.0 mmol). The reaction mixture was thoroughly stirred for 1 hour at ambient temperature until it began to transform to a viscous state, then washed with diethyl ether (3 x 5 mL). The product is obtained as a bright yellow powder. Yield: 95% (5.74 g, 9.5 mmol). * Interaction between 1 and 2-aminopyridine The reaction of 1 with 2-aminopyridine (NH2-Py) was carried out by changing some reaction conditions such as solvent and experiment manipulation. Based on the product’s characteristics and IR spectra, it can be concluded that the products of the experiments are the same and denoted 2. The procedure to produce 2 with the highest yield is described as follows: 2-aminopyridine (94 mg, 1.0 mmol) in 5 mL ethanol was added gradually to a mixture of 1 (604 mg, 1.0 mmol) in ethanol (5 mL). The mixture was stirred at 25÷30 o C for 4 hours. The reaction mixture was then filtered through Celite, and the residue was repeatedly washed by ethanol until the filtrate was colorless. The solvent of the filtrate was removed under vacuum to give solids, which were subsequently washed with warm water (3 × 3 mL) and cold ethanol (2 × 2 mL). Drying the solids under vacuum for 2 hours afforded the expected products as a yellow powder. Yield: 85% (530 mg, 0.85 mmol). * Interaction between 1 and 2-(aminomethyl)pyridine 2-(aminomethyl)pyridine (110 mg, 1.0 mmol) in an aqueous acetone solution (10 mL, 1:1, v/v) was added gradually to a mixture of 1 (604 mg, 1.0 mmol) in water (5 mL). The mixture was stirred at 25÷30 o C for 3 hours. After cooling the reaction mixture in an ice bath at about 5 o C for 30 minutes, a brown precipitate labeled 3 was filtered off, washed consecutively with water (3 x 2 mL), ethanol (2 × 2 mL) and acetone (2 x 5 mL), then dried under vacuum at 45 o C for 3 hours. The IR and 1 H NMR spectra show that the product 3 is a mixture of two complexes (3A and 3B), so the efficiency was not calculated. 2.1.2. Apparatus and methods Pt and water of hydration proportion were determined using weight method [10] at Department of Chemistry, Hanoi National University of Education. The EDX spectrum of 3 Pham Van Thong, Truong Thi Cam Mai, Nguyen Thi Thanh Chi 20 was recored on JED-2300 at Institute Materials Sciences. The IR spectra were recorded on IMPACK-410 NICOLET spectrometer in KBr discs in the range 400÷4000 cm -1 ; The 1 H NMR spectra were recorded on Bruker AVANCE 500 MHz (all at 298-300 K with TMS as internal standard in suitable solvent) at Vietnam Academy of Science and Technology. 2.2. Results and discussion According to [6], complex K[PtCl3( i PrEug)] (1) was synthesized by the reaction between Zeise’s salt and isopropyl eugenoxyacetate at 40÷45 oC in a acetone - propan-2- ol mixture, the reaction was carried out for 5 hours. In this study, the procedure of producing 1 has been improved, the reaction happens at room temperature for 1 hour without solvent (see experimental) with the same yield, 95%. The reaction equation is described in scheme (1). Scheme 1. Reaction equation for preparation of K[PtCl3( i PrEug)] (1) The IR and 1 H NMR spectra of 1 were measured and compared with those in the reference [6], the results are the same. Complex 1 was used as a starting compound to study interaction with either 2-aminopyridine or 2-(methylamino)pyridine. 2-aminopyridine ligand can coordinate with Pt(II) through two coordinating centers, N heteroatom and N of NH2 group. Concerning the NH2 group, a pair of electrons of N atom conjugates with pyridine ring but it is still able to coordinate with Pt(II). Meanwhile, the N atom of pyridine ring possesses a lone pair of electrons which is sp 2 hybridized, making the N atom easier to coordinate with Pt(II). Thus we propose the reaction equation of 1 and 2-aminopyridine as scheme (2): Scheme 2. Reaction equation for preparation of trans-[PtCl2( i PrEug)(NH2Py)] (2) Based on analysis of the IR and 1 H NMR spectra, it can be determined that NH2Py in 2 coordinates with Pt(II) through the N heteroatom as proposed in scheme (2). This type of coordination of NH2Py was also observed when it reacted with K[PtCl3(methyl eugenoxyacetate)] or K[PtCl3(ethyl eugenoxyacetate)] [11, 12]. Additionally, we assume that 2 has a trans configuration, which is reasonable to the trans effect. So far, there has not been any studies on interaction between 2- (methylamino)pyridine ligand with complex of the general formula K[PtCl3(olefin)]. This ligand also has two coordinating centers, N atom of pyridine ring and N atom of NH2 The interaction between K[PtCl3(isopropyl eugenoxyacetate)] with pyridine’s derivatives 21 group. However, these two N atoms are in 3 sigma bonds apart from each other resulting in tendency to form five-membered ring complex. Therefore, we suppose that when NH2CH2Py reacts with 1, it will cleave the Pt- i PrEug bond and one of the three Pt-Cl bonds to afford a neutral chelating complex [PtCl2(NH2CH2Py)] (3A). However, the EDX, IR and 1 H NMR spectra indicate that the product is a mixture of two complexes [PtCl2(NH2CH2Py)] (3A) and [PtCl2(NH2CH2Py)2] (3B) as described in scheme 3. We have not yet separated 3A and 3B from the mixture after many trials since 3A and 3B (the mixture) are both only soluble in DMSO (Table 1). Scheme 3. Reaction equation for preparation of a mixture of 3A and 3B To determine the composition and structure of 2 and 3, we have used weight method, and EDX, IR, 1 H NMR spectroscopies. The results from analyzing water of hydration proportion shows that in 2 and 3 there contain no water of hydration. Percentage of Pt found in 2 by the weight method is 30.56% compatible with the calculated value (31.25%) from the formula [PtCl2 ( i PrEug)(NH2Py)]. For complex 3, the actual percentage of Pt is not in accordance with the calculated value from the formula [PtCl2(NH2CH2Py)], while the atomic ratio of Pt : Cl determined by EDX spectroscopy in different areas of the sample is 1: 1.83. We assume that 3 is a mixture of two complexes [PtCl2(NH2CH2Py)] (3A) and [PtCl2(NH2CH2Py)2] (3B). This assumption is further elucidated by the IR and 1 H NMR spectra. Table 1. % Pt, H2O, atomic ratio of Pt: Cl and solubility of 2 and 3 Complexes % (Found /Calc.) Atomic ratio of Pt : Cl (Found/Calc.) Solubility (at RT) Pt H2O water ethanol acetone CHCl3 DMS O [PtCl2( i PrEug)(NH2Py)] (2) 30.56 31.25 0 0 - insoluble slightly soluble soluble soluble soluble [PtCl2(NH2CH2Py)] (3A) and [PtCl2(NH2CH2Py)2] (3B) - 0 0 1.00 :1.83 1.00 : 2.00 insoluble insoluble slightly soluble slightly soluble soluble Main bands in the IR spectra of the examined complexes are listed in Table 2. In the IR spectrum of 2, there is a characteristic band at 1742 cm -1 for νC=O indicating the presence of iPrEug. To be specific, the frequency of band for νC=Callyl in i PrEug has decreased from 1640 cm -1 in the free ligand to 1633 ÷ 1505 cm -1 in 2 showing that i PrEug has coordinated with Pt(II) via the C=Callyl. In addition, the IR spectrum displays two intensive bands at Pham Van Thong, Truong Thi Cam Mai, Nguyen Thi Thanh Chi 22 3430 ÷ 3331 cm -1 corresponding to symmetric and asymmetric stretching vibrations of NH2 group of free NH2Py and a characteristic band for νPt-N at 613 cm -1 showing that NH2Py in 2 coordinates with Pt(II) through only N atom of the pyridine ring. Table 2. Main bands in the IR spectra of 2 and 3, cm -1 Complexes NH CH aromatic CH aliphatic C=O δNH2, (C=C, C=N) Pt-N (Pt-C=C) [PtCl2( i PrEug)(NH2Py)] (2) 3430; 3331 3000 2987; 2938 1742 1633; 1598 1505 613 496 [PtCl2(NH2CH2Py)] and [PtCl2(NH2CH2Py)2] (3) 3457; 3490 3224; 3150 2950 2936; 2850 - 1614 1590; 1495 644 545 - In the IR spectrum of 3, there are two bands at 3224 ÷ 3150 cm -1 and two bands at 3490 ÷ 3457 cm -1 characteristic for NH2 group in both the coordinated and free NH2CH2Py, while the characteristic band for C=O of i PrEug at around 1740 cm -1 is not observed. These suggest that NH2CH2Py has replaced i PrEug in 1 to form a mixture of two complexes (3), [PtCl2(NH2CH2Py)] (3A) and [PtCl2(NH2CH2Py)2] (3B). In which, NH2CH2Py coordinates with Pt(II) via N atom of NH2 group for the former but not for the later. Table 3. 1 H NMR signals of i PrEug, NH2-Py in the free ligands and in 2,  (ppm), J (Hz) Comp. (acetone-d6) H3 H5 H6 H7a H7b H8a H8b H9 H10cis Free 6.85 6.69 6.83 4.61 3.81 3.32 5.96 5.05 2 7.22 d 4 J 1.5 7.01 dd 3 J 8 4 J 1.5 6.93 d 3 J 8 4.69 s 3.85 s 3.24 dd 2 J 15 3 J 6 3.53 dd 2 J 15 3 J 6 5.82 m 2 JPtH 70 4.61 3 J 11 2 JPtH 72 H10trans H11 H12 H13 H14 H15 H16 NH2 Free 5.01 5.08 1.23 6.48 7.41 6.63 8.06 4.45 2 4.71 d 3 J 15.5 2 JPtH 70 5.08 m 1.25 d 3 J 6.5 6.78 d 3 J 9.0 7.56 m 6.72 m 7.89 d 3 J 5.5 6.23 br To clarify coordination of the ligands in the examined complexes, 1 H NMR spectroscopy was used. The numeration of i PrEug, NH2Py and NH2CH2Py in the scheme 1÷3 is used for the 1 H NMR analysis. The assignment of the 1 H NMR spectra is based on their chemical shift (δ), intensity, spin-spin splitting pattern (shape) and value of splitting constant (J). The result of analyzing 1 H NMR spectrum of 2 is listed in Table 3. Table 3 shows the resonances for all protons of i PrEug and NH2Py in 2 which are different from the non-coordinated ligands. Upon coordination to Pt(II), the resonances of the olefinic protons (H9, H10cis and H10trans) shift upfield in comparison to those of free i PrEug. The 195 Pt satellites from these protons are clear with the distance between them, 2 JPtH = 70 - 72 Hz, indicating that the allyl of i PrEug is an η2 coordinated olefin. This coordination results in the inequivalence of 2H8 which are equivalent in the free ligand. The interaction between K[PtCl3(isopropyl eugenoxyacetate)] with pyridine’s derivatives 23 In the 1 H NMR spectrum of 3, there are two sets of proton signals with ratio of 2 : 1 calculated from the intergrals. Each of them contains 8 signals for protons of 2- (aminomethyl)pyridine. The signals were assigned as shown in Figure 1 and Table 4. Figure 1. Assigned 1 H NMR spectrum of 3 (a mixture of 3A and 3B) Table 4. 1 H NMR signals of NH2CH2Py in the free ligand and in 3,  (ppm), J (Hz) The results of analyzing the EDX and IR spectra of 3 above have proved that 3 is a mixture of [PtCl2(NH2CH2Py)] (3A) and [PtCl2(NH2CH2Py)2] (3B). Based on the values of  of the two sets of signals, we suppose that the set with higher intensity belongs to 3A, and the left one belongs to 3B. This can be explained as follows: NH2CH2Py in 3A coordinates with Pt(II) via both N atoms of the pyridine ring and NH2 group while it only coordinates with Pt(II) via N atom of the pyridine ring in 3B. This leads the magnitude of  of the signals corresponding to 3A higher than that of 3B, especially H17 and H(NH2) (Table 4). The resonances of the amine protons in both 3A and 3B are downfield in comparison to those of the free amine (Table 4) indicating that the amine has coordinated with Pt(II). Moreover, from the intensity ratio of 3A:3B in the 1 H NMR spectrum is 2:1, Amin H13 H14 H15 H16 H17 NH2 Free 7.15 7.62 7.26 8.55 1.84 3,97 3A 7.85 d 3 J 8 8.26 m 7.69 t 3 J 7.0 8.93 d 3 J 5.5 4.42 t 3 J 5.5 6,82 s 3B 7.63 d 3 J 8 8.11 m 7.48 t 3 J 7.0 9.08 d 3 J 5.5 4.08 t 3 J 5.5 6.18 s Pham Van Thong, Truong Thi Cam Mai, Nguyen Thi Thanh Chi 24 it is induced that 3 is a mixture of 3A and 3B with the molar ratio of 4:1. In addition, the equivalence of two 2-(aminomethyl)pyridine molecules in 3B shows that it has a trans configuration. Complex 2 was tested for cell in vitro cytotoxicity on cancer cell line KB (Human epidemic carcinoma). The result shows that 2 exhibits high cytotoxic activity against this cell line with IC50 value of 10.5 μg/mL. 3. Conclusion The interactions of K[PtCl3( i PrEug)] (1) with either 2-aminopyridine (NH2Py) or 2- (aminomethyl)pyridine (NH2CH2Py) have been studied for the first time. The results show that 2-aminopyridine replaces one of the three Cl atoms present in 1 to form trans- [PtCl2( i PrEug)(NH2Py)] (2), while 2-(aminomethyl)pyridine replaces not only one of the three Cl atoms but also i PrEug (isopropyl eugenoxyacetate) to form a mixture (3) of [PtCl2(NH2CH2Py)] (3A) and trans-[PtCl2(NH2CH2Py)2] (3B). The structure of 2 and 3 were determined by means of platinum analysis, EDX, IR and 1 H NMR spectroscopy. In 2, i PrEug coordinates with Pt(II) through ethylenic double bond of the allyl group, and NH2Py coordinates with Pt(II) via the N atom of pyridine ring. The ligand NH2CH2Py coordinates with Pt(II) via both the N heterocyclic atom and NH2 group in 3A but only coordinates with Pt(II) via N atom of the pyridine ring in 3B. Complex 2 exhibits high cytotoxic activity against KB cancer cell line with IC50 value of 10.5 μg/mL. REFERENCES [1] Timothy C. Johnstone, Kogularamanan Suntharalingam, and Stephen J. Lippard, 2016. 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