Polyhedron 85 (2015) 104–109

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Polyhedron

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Synthesis, structure and properties of two series of platinum(II)complexes containing methyleugenol or chelating methyleugenoland amine

http://dx.doi.org/10.1016/j.poly.2014.08.0450277-5387/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Address: DHSP Ha Noi, 136 Xuan Thuy, Hanoi, Viet Nam.Tel.: +84 04 37560196.

E-mail address: huudinhhnue@gmail.com (N.H. Dinh).

Tran Thi Da a, Nguyen Thi Thanh Chi a, Luc Van Meervelt b, Peter Mangwala Kimpende b,Nguyen Huu Dinh a,⇑a Department of Chemistry, Hanoi National University of Education, 136 Xuan Thuy, Hanoi, Viet Namb Biomolecular Architecture, Chemistry Department K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium

a r t i c l e i n f o a b s t r a c t

Article history:Received 20 March 2014Accepted 13 August 2014Available online 26 August 2014

Keywords:Platinum complexMethyleugenolTrans-effectAmineCytotoxicity

Two series of platinum(II) complexes of the formula [PtCl2(Meug)(Amine)] (1–6, Meug: methyleugenol)and [PtCl(Meug-1H)(Amine)] (7–13, Meug-1H: deprotonated methyleugenol) were synthesized and char-acterized by elemental analyses, IR, 1H NMR, 13C NMR, NOESY and XRD spectra. In complexes 1–6 themethyleugenol ligand coordinates to Pt(II) through the ethylenic double bond of the allyl group, and theamine is in the trans-position in comparison to the ethylenic double bond. In complexes 7–13 the chelatingmethyleugenol ligand is bound to Pt(II) both through the ethylenic double bond of the allyl group and viaan aromatic carbon. NOESY spectra and single-crystal X-ray diffraction of [PtCl(Meug-1H)(o-toluidine)](14) indicate that in 7–14 the amines are in a cis-position with respect to the ethylenic double bond.[PtCl2(Meug)(Pyridine)] (4), [PtCl2(Meug)(Quinoline)] (5) and [PtCl(Meug-1H)(Quinoline)] (9) exhibitstrong activities on human cancer cells KB with IC50 values of 3.7, 3.4 and 3.2 lg/mL respectively.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction been characterized, showing favorable cytotoxicity against cancer

Studies in recent years have shown that the range of platinumcomplexes with useful cytotoxicity and antitumor activities is notstrictly limited to structural analogs of cisplatin, and not all plati-num-containing drugs need necessarily be similar in their mecha-nism of action to cisplatin [1]. Thus, a variety of studies have dealtwith non-classical complexes, showing favorable cytotoxicityagainst cancer cells. For example, a platinum(II) complex with onenormal and one cyclometallated 2-phenylpyridine ligand was dis-covered that exhibited high antitumor efficacy against cisplatin-resistant mouse sarcoma 180 (S-180cisR) cell lines [2]. Quirogaet al. reported the synthesis and characterization of two new metal-lic complexes derived from phenylacetaldehyde thiosemincarbaz-one, Pt(C9H11N3S)Cl2 and Pd(C9H11N3S)Cl2, and suggested that thecompounds may be considered as potential anticancer agents sincethey exhibit IC50 values in a mM range similar to cisplatin [3]. Somecomplexes of platinum(II) with natural compounds have been syn-thesized and their antitumor and antiviral activities have been dem-onstrated [4,5]. Several classes of trans platinum complexes have

cells, especially cisplatin-resistant cells [6].Methyleugenol (4-allyl-1,2-dimethoxybenzene) is a natural

constituent of a number of plants, such as cinnamomum cordatum,nutmeg, pimento, lemongrass, tarragon, holy basil, star anise andfennel. Methyleugenol is used in perfumery and flavoring, in for-mulating insect attractants, UV absorbers, analgesics, biocides[7–10] and psychotropic drugs [11]. It is, therefore, worthwhileto introduce methyleugenol, a natural arylolefin, into the platinumcoordination sphere and then chemically to transform the receivedcomplexes into biologically active compounds. In a previous paper[12] we described a series of platinum(II) complexes containingmethyleugenol and some amines. Herein we report the synthesis,structure and properties of two other series of platinum(II) com-plexes containing methyleugenol or chelating methyleugenol andvarious amines in order to find out if the resulting compounds haveany useful cytotoxicity.

2. Experimental

2.1. Materials and instrumentation

All amines and solvents were reagent or analytical grade andused as received. IR spectra were recorded on an IMPACK-410

T.T. Da et al. / Polyhedron 85 (2015) 104–109 105

NICOLET spectrometer in KBr discs from 400 to 4000 cm�1. NMRspectra were recorded on a Bruker AVANCE 500 MHz at 298–300 K, in a suitable solvent (Tables 1 and 2), with TMS as the inter-nal standard. Pt was analyzed according to the weight method [13],C and H were analyzed on a LECO CHNS model 932 elemental ana-lyzer. Single-crystal X-ray diffraction data for 14 were recorded inK.U. Leuven (Belgium) on a Bruker SMART6000 diffractometer(fine-focus sealed tube, Cu Ka radiation, crossed Göbel mirrors)at 100 K. The intensity data were corrected for Lorentz and polar-ization effects, and for absorption (SADABS) [14]. The structure wassolved by direct methods (SHELXS-97) [15] and refined by full-matrixleast-squares based on F2 using SHELXL-97 [16]. Hydrogen atomswere located in calculated positions. The anticancer activities weretested at the Experimental Biological Laboratory – Institute ofChemistry of Natural Compounds (in Hanoi), according to thedescribed method [17]; IC50 values were calculated based on ODvalues taken on an Elisa instrument at 515–540 nm.

2.2. Preparation of complexes 1–6

To a solution of K[PtCl3(Meug)] (260 mg, 0.5 mmol, previouslyprepared [12], Meug: methyleugenol) in 15 mL ethanol/water(3:2 by volume), an amine (0.5 mmol) in 15 mL ethanol/water(3:2 by volume) was slowly added and the resulting mixture wasstirred at room temperature for an hour. The precipitate thatformed was collected, washed with a solution of 0.1 N HCl, water,cold ethanol and dried in a vacuum at 50 �C for 2 h.

2.2.1. [PtCl2(Meug)(PhNH2)] (1)The yield was 220 mg (82%), light yellow crystals. Anal. Calc. for

[PtC17H21Cl2NO2]: Pt, 36.30; C, 38.00; H, 3.94. Found: Pt, 36.58; C,37.75; H, 3.78%. IR (cm�1): 3220, 3141 (m NH); 3038, 2998, 2841,2838 (m CH); 1579, 1511 (m C@C). For 1H NMR see Table 1. 13CNMR (CD3COCD3) d: 149.06, 150.39, 113.12, 132.17, 121.82,113.93 (C1–C6); 56.21, 56.09 (C1a, C2a); 39.78, 101.08, 70.07 (C7,C8, C9); 147.16 (C11); 130.13 (C12/C16); 128.02 (C13/C15); 124.46(C14).

2.2.2. [PtCl2(Meug)(4-O2NPhNH2)] (2)The yield was 248 mg (85%), yellow crystals. Anal. Calc. for

[PtC17H20Cl2N2O4]: Pt, 33.50; C, 35.06; H, 3.46. Found: Pt, 33.77;C, 34.78; H, 3.18%. IR (cm�1): 3256, 3192 (m NH); 3000, 2937,

Table 11H NMR signals of complexes 1–6, d (ppm), J (Hz).

Compd.Solvent

1 (CD3)2CO 2 CD3OD 3 CDCl3

Am

NH216

12131415

NH216

1213

15O2N NH2

16

1213

15I

H3 6.95 s 7.01 s 6.85 sH5 6.92 d; 3J 8 6.88 d; 3J 8 6.82 d; 3J 8H6 6.79 d; 3J 8 6.80 d; 3J 8 6.74 d; 3J 8H1a 3.79 s 3.81 s 3.87 sH2a 3.77 s 3.79 s 3.81 sH7a 3.10 dd; 2J 15; 3J 6; 3JPtH 50 2.99 dd; 2J 16; 3J 5; 3JPtH 50 3.08 mH7b 3.46 dd; 2J 15; 3J 8 3.33 m 3.43 dd; 2J 15; 3J 7H8 5.53 m 2JPtH 75 5.47 m 2JPtH 75 5.57m 2JPtH 75H9cis 4.44 d; 3J 8; 2JPtH 65 4.39 d; 3J 8; 2JPtH 70 4.56 mH9trans 4.52 d; 3J 14; 2JPtH 65 4.53 dd; 3J 14; 2JPtH 70 4.64 d; 3J 14;H12 7.23 d; 3J 7 7.14 d; 3J 9 7.15 d; 3J 6H13 7.45 t; 3J 7 8.07 d; 3J 9 7.67 d; 3J 6H14 7.38 t; 3J 8 – –H15 7.45 t; 3J 7 8.07 d; 3J 9 7.67 d; 3J 6H16 7.23 d; 3J 7 7.14 d; 3J 9 7.15 d; 3J 6Others – – 5.80 broadened s.

2845 (m CH); 1592, 1522 (m C@C). For 1H NMR see Table 1. 13CNMR (CD3OD) d: 149.85, 150.76, 113.86, 133.42, 122.15, 114.23(C1–C6); 56.591, 56.31 (C1a, C2a); 39.26, 101.79, 71.11 (C7, C8, C9);147.43 (C11); 130.98 (C12/C16); 127.74 (C13/C15); 148.36 (C14).

2.2.3. [PtCl2(Meug)(4-INPhNH2)] (3)The yield was 265 mg (80%), light yellow crystals. Anal. Calc. for

[PtC17H20Cl2INO2]: Pt, 29.41; C, 30.79; H, 3.04. Found: Pt, 29.65; C,30.58; H, 2.88%. IR (cm�1): 3263, 3206 (m NH); 3071, 2951, 2838 (mCH); 1588, 1515 (m C@C). For 1H NMR see Table 1. 13C NMR(CD3COCD3) d: 147.28, 148.89, 110.23, 133.57, 122.89, 109.13(C1–C6); 56.35, 56.12 (C1a, C2a); 39.65, 101.56, 70.24 (C7, C8, C9);146.25 (C11); 138.26 (C12/C16); 126.42 (C13/C15); 98.56 (C14).

2.2.4. [PtCl2(Meug)(Pyridine)] (4)The yield was 238 mg (91%), light yellow crystals. Anal. Calc. for

[PtC16H19Cl2NO2]: Pt, 37.28; C, 36.72; H, 3.66. Found: Pt, 37.55; C,36.95; H, 3.38%. IR (cm�1): 3110, 2960, 2839 (m CH); 1605, 1513(m C@C). For 1H NMR see Table 1. 13C NMR (CD3COCD3) d: 149.27,150.52, 113.19, 132.23, 121.87, 113.99 (C–C6); 56.18, 56.12 (C1a,C2a); 40.44, 101.94, 69.08 (C7, C8, C9); 152.17 (C12/C16); 126.76(C13/C15); 150.52 (C14).

2.2.5. [PtCl2(Meug)(Quinoline)] (5)The yield was 250 mg (87%), yellow crystals. Anal. Calc. for

[PtC20H21Cl2NO2]: Pt, 34.02; C, 41.90; H, 3.69. Found: Pt, 34.26; C,41.62; H, 3.48%. IR (cm�1): 3077, 3000, 2955, 2834 (m CH); 1592,1512 (m C@C). For 1H NMR see Table 1. 13C NMR (CD3COCD3) d:149.25, 150.61, 113.33, 131.16, 122.19, 114.43 (C1–C6); 56.29,56.12 (C1a, C2a); 40.18, 102.50, 70.33 (C7, C8, C9); 153.57, 128.95,141.31, 128.95, 123.06, 132.05, 129.08, 146.50, 131.16 (C12–C20).

2.2.6. [PtCl2(Meug)(2-MeQuinoline)] (6)The yield was 269 mg (90%), light yellow crystals. Anal. Calc. for

[PtC20H21Cl2NO2]: Pt, 34.02; C, 41.90; H, 3.69. Found: Pt, 34.26; C,41.62%; H, 3.48. IR (cm�1): 3077, 3000, 2955, 2834 (m CH); 1592,1512 (m C@C). For 1H NMR see Table 1. 13C NMR (CD3COCD3) d:149.02, 150.54, 113.34, 131.64, 122.14, 114.36 (C1–C6); 56.29,56.06 (C1a, C2a); 39.84, 100.67, 70.56 (C7, C8, C9); 162.55, 128.26,141.12, 128.17, 125.62, 131.64, 129.03, 146.89, 129.31, 26.63(C12–C21).

4 (CD3)2CO 5 (CD3)2CO 6 (CD3)2CO

N16

12131415

16

12

131415

N17

19

2016

2113

1415

N17

19

20

Me7.17 d; 4J 2 7.24 d; 4J 2 7.19 d; 4J 27.03 dd; J 8; 2 7.12 dd; J 8; 2 7.06 dd; J 8; 26.94 d; 3J 8 7.04 d; 3J 8 7.02 d; 3J 83.81 s 3.88 s 3.88 s3.80 s 3.78 s 3.77 s3.25 dd; 2J 15; 3J 7; 3JPtH 50 3.31 dd; 2J 15; 3J 6; 3JPtH 50 3.32 d; 2J 153.62 dd; 2J 15; 3J 7 3.60 dd; 2J 15; 3J 9 3.57 dd; 2J 15; 3J 85.75 m 2JPtH 75 5.62 m 2JPtH 70 5.84 m 2JPtH 754.61 d; 3J 8; 2JPtH 70 4.72 d; 3J 8; 2JPtH 70 4.77 d; 3J 8; 2JPtH 704.77 d; 3J 14; 2JPtH 70 4.82 d; 3J 14; 2JPtH 70 4.86 d; 3J 14; 2JPtH 708.82 d; 3J 4 9.07 s; 3JPtH 35 H21: 3.30 s7.73 t; 3J 7 7.76 m 7.67 d; 3J 88.17 tt; J 7; 2 8.68 d; 3J 8 8.54 d; J 87.73 t; 3J 7 8.14 d; 3J 8 8.06 d; 3J 88.82 d; 3J 4 7.79 m 7.70 t; 3J 8– H17: 7.81 m; H18:

8.78 brd. sH17: 7.76 m; H18:9.21 brd. s

Table 21H NMR signals of complexes 7–13, d (ppm), J (Hz).

Compd.Solvent

7 CDCl3 8 CDCl3 9 (CD3)2CO 10 CDCl3 11 (CD3)2CO 12 (CD3)2CO 13 CD3OD

Amine

NH216

12131415

17NH2

16

1213

15Me 16

12

131415

N17

19

2016

2113

1415

N17

19

20

MeO NH

16

1213

15161213

15NH

12Me-NH2

H3 6.51 s 6.50 s 6.67 s 6.64 s 6.58 s 6.59 s 6.61 sH6 7.01 s 3JPtH 40 7.02 s 3JPtH 40 7.16 s 3JPtH 40 7.26 s 3JPtH 40 6.99 s 3JPtH 39 7.05 s 3JPtH 39 6.83 s 3JPtH 39H1a 3.85 s 3.83 s 3.77 s 3.94 s 3.72 s 3.72 s 3.63 sH2a 3.76 s 3.75 s 3.72 s 3.82 s 3.67 s 3.67 s 3.62 sH7a 2.42 d; 2J 17; 3JPtH

1052.39 d; 2J 17; 3JPtH 105 2.67 d; 2J 16; 3JPtH

1052.65 d; 2J 16; 3JPtH 105 2.55 d; 2J 16

3JPtH 1052.62 d; 2J 163JPtH 110

2.51 d; J163JPtH 110

H7b 3.60 dd; 2J 17; 3J 6 3.59 dd; 2J 17; 3J 6 3.85 dd; 2J 16; 3J 6 3.45 dd; 2J 16; 3J 7 3.58 dd; 2J 16; 3J6

3.63 dd; 2J 16;3J 6

3.55 dd; 2J 16;3J 6

H8 4.14 m 2JPtH 70 4.16 m 2JPtH 70 4.74 m 2JPtH 70 4.49 m 2JPtH 70 4.74 m 2JPtH 70 4.62 m 2JPtH

724.70 m 2JPtH

72H9cis 3.42 d; 3J 7 2JPtH 75 3.43 d; 3J 7 2JPtH 75 3.67 d; 3J 6 2JPtH 75 3.90 d;3J 6 2JPtH 75 3.93 d; 3J 7 2JPtH

783.80 d; 3J 72JPtH 70

3.88 d; 3J 72JPtH 75

H9trans 3.70 d;3J 13 3.65 d; 3J 13 3.92 d; 3J 13 4.02 d; 3J 13 3.62 d; 3J 14 3.72 d; 3J 15 3.47 d; 3J 13H12 7.02 d; 3J 8 6.90 d; 3J 8 9.20 s – a:3.27 qd⁄ e:

2.94 d3.08 m 2.30 t; 3J 6.5

H13 7.34 t; 3J 8 7.09 d; 3J 8 7.56 m 7.43 d; 3J 8 a: 3.64 m e:3.80 dd⁄

1.40 t; 3J 7 –

H14 7.15 t; 3J 8 – 8.64 d; 3J 8 8.22 d; 3J 8 – – –H15 7.34 t; 3J 8 7.09 d; 3J 8 8.16 d; 3J 8 7.86 d; 3J 8 a: 3.64 m e:

3.80 dd⁄1.37 t; 3J 7 –

H16 7.02 d; 3J 8 6.90 d; 3J 8 7.78 t; 3J 8 7.61 t; 3J 8 a: 3.25qd; ⁄ e:2.91 d

2.96 m –

Others HaN: 4.86 d HbN:4.57 d 2J 11

HaN: 4.87 d HbN: 4.62 d; 2J11 H17: 2.32 s

H17: 8.02 t; 3J 8 H18:9.19 brd. s

H17: 7.88 t; 3J 8 H18 9.57brd. s H21: 3.28 s

HN: 4.01broadened s. ⁄):2J ae 12; 3J ee 3;3J aa 12

HN: 3.34broadened s.

HN: 3.53broadened s.

106 T.T. Da et al. / Polyhedron 85 (2015) 104–109

2.3. Preparation of complexes 7–13

2.3.1. [PtCl(Meug–1H)(PhNH2)] (7)Phenylamine (75 mg, 0.8 mmol) dissolved in10 mL CHCl3 was

slowly added with stirring to a suspension of 326 mg (0.4 mmol)[Pt2Cl2(Meug–1H)2] (previously prepared [18], Meug-1H: deproto-nated methyleugenol) in 10 mL CHCl3. The reaction mixture wasstirred at room temperature for 2 h. The resulting precipitate wascollected, washed with cold ethanol, diethyl ether and dried in avacuum at 50 �C for 2 h. The yield was 256 mg (65%), white crystal-line solid. Anal. Calc. for [PtC17H20ClNO2]: Pt, 38.95; C, 40.76; H,4.02. Found: Pt, 38.76; C, 41.02; H, 3.85%. IR (cm�1): 3237, 3145(m NH); 3060, 2996, 2940, 2834 (m CH); 1598, 1488 (m C@C). For1H NMR see Table 2. 13C NMR (CDCl3) d: 145.15, 147.46, 108.25,139.36, 120.13, 116.82 (C1–C6); 55.94, 55.88 (C1a, C2a); 37.89,89.25, 62.32 (C7, C8, C9); 140.85 (C11); 129.49 (C12/C16); 125.21(C13/C15); 121.62 (C14).

2.3.2. [PtCl(Meug-1H)(4-MePhNH2)] (8)This complex was prepared starting with 86 mg (0.8 mmol) 4-

methylphenylamine, according to the procedure for the prepara-tion of 7. The yield was 272 mg (68%), white crystalline solid. Anal.Calc. for [PtC18H22ClNO2]: Pt, 37.89; C, 41.99; H, 4.31. Found: Pt,38.16; C, 41.71; H, 4.13%. IR (cm�1): 3238, 3145 (m NH); 3003,2931, 2908, 2830 (m CH); 1597, 1489 (m C@C). For 1H NMR seeTable 2. 13C NMR (CDCl3) d: 145.13, 147.40, 108.23, 136.65,120.01, 116.85 (C1–C6); 55.93, 55.86 (C1a, C2a); 37.88, 89.12,62.27 (C7, C8, C9); 140.89 (C11); 134.79 (C12/C16); 129.93(C13/C15); 121.92 (C14); 20.80 (C17).

2.3.3. [PtCl(Meug–1H)(Quinoline)] (9)A solution of 104 mg (0.8 mmol) quinoline in 10 mL acetone

was slowly added with stirring to a suspension of [Pt2Cl2(Meug-1H)2] (326 mg, 0.4 mmol) in 10 mL acetone and 10 mL ethanol.

The reaction mixture was stirred at room temperature for 2 h.The resulting precipitate was collected, washed with cool ethanol,diethyl ether and dried in a vacuum at 50 �C for 2 h. The yield was348 mg (81%), white crystalline solid. Anal. Calc. for [PtC20H20-

ClNO2]: Pt, 36.33; C, 44.74; H, 3.75. Found: Pt, 36.05; C, 45.02; H,3.52%. IR (cm�1): 3060, 3017, 2903, 2838 (m CH); 1586, 1507,1470 (m C@C). For 1H NMR see Table 2. 13C NMR (CD3COCD3) d:146.85, 147.36, 108.50, 139.45, 123.46, 116.20 (C1–C6); 56.39,55.30 (C1a, C2a); 39.31, 110.09, 67.10 (C7, C8, C9); 153.57, 119.36,140.07, 129.59, 128.77, 131.96, 128.75, 141.50, 128.47 (C12–C20).

2.3.4. [PtCl(Meug–1H)(2-MeQuinoline)] (10)This complex was prepared starting with 115 mg (0.8 mmol) 2-

methylquinoline, according to the procedure for the preparation of9. The yield was 353 mg (80%), white crystalline solid. Anal. Calc.for [PtC21H22ClNO2]: Pt, 35.41; C, 45.78; H, 4.02. Found: Pt,35.66; C, 46.02; H, 3.85%. IR (cm�1): 3069, 2984, 2934, 2835 (mCH); 1588, 1483, 1465 (m C@C). For 1H NMR see Table 2. 13CNMR (CDCl3) d: 146.02, 146.63, 108.25, 139.14, 124.20, 116.74(C1–C6); 56.01, 55.93 (C1a, C2a); 38.74, 87.45, 60.90 (C7, C8, C9);161.33, 127.17, 139.93, 127.57, 124.49, 131.09, 127.75, 138.92,128.34, 26.25 (C12–C21).

2.3.5. [PtCl(Meug–1H)(Morpholin)] (11)A solution of 87 mg (1 mmol) morpholin in 2 mL ethanol was

added with stirring to a suspension of [Pt2Cl2(Meug–1H)2](408 mg, 0.5 mmol) in 6 mL ethanol. The obtained solution wasput standing at room temperature for 1 h. The resulting precipitatewas collected, washed with cool ethanol, cool diethyl ether anddried in a vacuum at 50 �C for 2 h. The yield was 258 mg (52%),light yellow crystals. Anal. Calc. for [PtC15H22ClNO3]: Pt, 39.42; C,36.41; H, 4.48. Found: Pt, 39.15; C, 36.68; H, 4.69%. IR (cm�1):3218 (m NH); 3060, 2953, 2903, 2838 (m CH); 1584, 1562, 1475 (mC@C). For 1H NMR see Table 2. 13C NMR (CD3COCD3) d: 146.27,

T.T. Da et al. / Polyhedron 85 (2015) 104–109 107

148.55, 110.00, 141.56, 125.59, 119.56 (C1–C6); 56.33, 56.22 (C1a,C2a); 39.16, 87.26, 60.33 (C7, C8, C9); 49.27, 48.59 (C12/C16); 68.14,68.06 (C13/C15).

2.3.6. [PtCl(Meug–1H)(Et2NH)] (12)This complex was prepared starting with 73 mg diethylamine

(1 mmol), according to the procedure for the preparation of 11.The yield was 193 mg (40%), light yellow crystals. Anal. Calc. for[PtC15H24ClNO2]: Pt, 40.57; C, 37.46; H, 5.03. Found: Pt, 40.78; C,37.62; H, 5.21%. IR (cm�1): 3224 (m NH); 3060, 2975, 2932, 2839(m CH); 1586, 1497 (m C@C). For 1H NMR see Table 2. 13C NMR (CD3-

COCD3) d: 145.54, 147.60, 109.19, 140.16, 124.00, 118.70 (C1–C6);55.68, 55.37 (C1a, C2a); 38.51, 86.11, 58.78 (C7, C8, C9); 46.84,46.52 (C12/C16); 13.77, 13.72 (C13/C15).

2.3.7. [PtCl(Meug–1H)(Methylamine)] (13)This complex was prepared starting with 0.1 mL of a 30%

methylamine water solution (1 mmol), according to the procedurefor the preparation of 11. The yield: 158 mg (36%), light yellowcrystals. Anal. Calc. for [PtC12H18ClNO2]: Pt, 44.46; C, 32.85; H,4.13. Found: Pt, 44.15; C, 33.07; H, 4.32. IR (cm�1): 3297 and3247 (m NH); 3003, 2952, 2900 and 2837 (m CH); 1588, 1471 (mC@C). For 1H NMR see Table 2. 13C NMR (CD3COCD3) d: 144.65,146.66, 108.84, 140.90, 127.78, 117.89 (C1–C6); 55.65, 55.59 (C1a,C2a); 38.33, 86.09, 59.82 (C7, C8, C9); 29.47 (C12).

2.3.8. [PtCl(Meug–1H)(2-MePhNH2)] (14)This complex was prepared starting with 86 mg (0.8 mmol)

2-methylphenylamine, according to the procedure for the prepara-tion of 7. The yield was 260 mg (65%). The IR and 1H NMR spectraof 14 coincide with those of the complex [PtCl(Meug–1H)(2-MePh-NH2)] which was described in [18]. Light yellow crystals suitablefor X-ray diffraction were obtained from an ethanol solution afterstanding for 7 days.

Crystal Data for 14, C18H22NO2ClPt (M = 514.91 g/mol): ortho-rhombic, space group P212121 (No. 19), a = 8.9207(2) Å,b = 10.0882(3) Å, c = 19.9866(5) Å, V = 1798.67(8) Å3, Z = 4,T = 100.15 K, l(CuKa) = 16.024 mm�1, Dcalc = 1.901 g/cm3, 18169reflections measured (8.84� 6 2h 6 142.98�), 3428 unique(Rint = 0.0533, Rr = 0.0332) which were used in all calculations.The final R1 value was 0.0194 (>2r(I)) and wR2 was 0.0467 (alldata).

3. Results and discussion

3.1. Synthesis of complexes 1–13

Complexes 1–13 were prepared as described in Fig. 1.The starting complexes K[PtCl3(Meug)] and [Pt2Cl2(Meug-1H)2]

(Meug: methyleugenol, Meug-1H: deprotonated methyleugenol)were prepared according to our procedure described in the refer-ences [12] and [18] respectively. The complexes 1–6 were preparedby replacement of a Cl ligand from K[Pt(Meug)Cl3] by an amine(Am). The reaction was carried out at 25–30 �C, the neutralcomplexes [Pt(Meug)(Am)Cl2] precipitate out and can be easily

Am

OO

OO

PtCl

ClCl

OO

PtCl

Am

9

1a

84

5

61

2

3

7

2a

Cl

K[PtCl3(Meug)](1 - 6)

11-21

Fig. 1. Reaction scheme for synthesis of complexes 1–13 (the numerat

isolated. The prepared complexes have a trans configuration, thatis obeying the trans effect.

It is known that the interaction of [Pt2(C2H4)2Cl4] and aminesgives trans-[Pt(C2H4)(Am)Cl2], as ethylene has a large trans effect.Surprisingly, in the reaction of [Pt2Cl2(Meug-1H)2] amines werenot introduced trans to the ethylenic double bond of the allylgroup, but were trans to C5 of the phenyl group to form complexes7–13 (Fig. 1), that is not seeming to obey the trans effect. It is pos-sible that this selectivity is controlled by steric effects rather thanthe trans effect.

3.2. Structures of the examined complexes

The IR spectra of 1–13 show bands for the coordinated methyl-eugenol and amine ligands. In addition, the absence of a band at1640 cm�1 from the C@C double bond of the allyl group in non-coordinated methyleugenol indicates the allyl group coordinatesin a g2 manner.

The assignment of the NMR signals is based on their chemicalshift and spin–spin splitting patterns. For ambiguous cases, NOESY,HSQS and HMBC spectra were also used. The 1H NMR signals of 1–6are listed in Table 1, and those of 7–13 are in Table 2. The 13C NMRsignals of 1–13 are given in the experimental section.

Upon coordination to Pt(II), the resonances of the ethylenic pro-tons (H8, H9cis, H9trans, Tables 1 and 2) shift upfield in comparison tothose of non-coordinated methyleugenol (5.86, 4.96, 4.98 ppm,respectively). The 195Pt satellites from H8, H9cis, H9trans are clear(indicated with ⁄ in Figs. 2 and 3) with the distance between them,2JPtH, being 65–75 Hz (Tables 1 and 2). The resonances of the ethyl-enic carbons C8 and C9 are upfield too. These indicate that the allylgroup of methyleugenol in 1–13 is present as a g2-coordinatedolefin.

For complexes 1–6, the phenyl group of the methyleugenolligand gives rise to three signals: H3, H5 and H6 with d(H3) >d(H5) > d(H6) (Table 1, Fig. 2), whilst for complexes 7–13, the phe-nyl group of the chelating methyleugenol ligand gives rise to twosignals: H3 and H6 with d(H3) < d(H6) (Table 2, Fig. 3). The H6-sin-glet is distinguished from the H3-singlet by 195Pt satellites with a3JPtH value of 39–40 Hz (Table 2, Fig. 3). This value is comparablein magnitude to 3JPtH in analogous platinum(II) complexes [18].The presence of these 195Pt satellites indicates that the coordinatedmethyleugenol ligand is bound to Pt(II) by a r-bond (C5–Pt), asshown in Fig. 1.

For non-coordinated methyleugenol, two protons, H7, give riseto a doublet at 3.22 ppm with 3J = 6.5 Hz, but in the spectra ofthe examined complexes there are two separated signals (usuallyin the form of a doublet of doublets) for H7a and H7b. This isexpected since upon coordination to Pt(II), the atom H8 becomesa chiral center, and H7a and H7b become diastereotopic.

In order to determine the configuration of the reportedcomplexes, their NOESY spectra were studied. For example, inthe spectrum of 6, there are no cross peaks between the protonsof 2-methylquinoline and the protons of methyleugenol, while inthe spectrum of 10, there are cross peaks between H18 of2-methylquinoline with H8 and H9cis of the allyl group,

PtCl

ClPt

OO

OO

PtAm

Cl

9

1a

84

5

61

2

3

711-21

2a

Am

[Pt2Cl2(Meug-1H)2] (7 - 13)

ion on these structures is specifically used for the NMR analysis).

Fig. 2. Expanded 1H NMR spectrum of complex 1.

Fig. 3. Expanded 1H NMR spectrum of complex 11.

108 T.T. Da et al. / Polyhedron 85 (2015) 104–109

simultaneously there are no cross peaks between the protons of 2-methylquinoline and H3 or H6 of the phenyl group of the chelatingmethyleugenol ligand. These show that for [PtCl(Meug) (2-MeQuinoline)] (6) 2-methylquinoline is in a trans-position, butfor [PtCl(Meug-1H)(2-MeQuinoline)] (10) it is in a cis-position incomparison to the ethylenic double bond, as shown in Fig. 1.

In addition, single-crystal X-ray diffraction for [PtCl(Meug-1H)(2-MePhNH2)] (14) was analyzed. The results show that the2-methylphenylamine ligand is cis to the allyl group. The two ben-zene rings of methyleugenol and 2-methylphenylamine are neithercoplanar nor perpendicular to the coordination plane of Pt(II) andmake an angle of 84.24(19)� with each other. One proton of theC7H2-group is adjacent to the Pt(II) atom. One proton of theNH2-group makes an H-bond with a neighboring Cl atom[N1� � �Cl1i: 3.466(4) Å, H1A� � �Cl1i: 2.56 Å, N1–H1A� � �Cl1i: 170�,symmetry code: (i) x � 1/2, �y + 1/2, �z] (Fig. 4).

It is interesting to note that the two protons of the amino groupin 7 and 8 give rise to two separate doublets (HaN and HbN, withthe roof effect and 2J = 11 Hz); in 12 two CH2 groups as well as

two CH3 groups of diethylamine give rise to two separate protonsignals and two 13C-signals; in 11 two C12H2 and C16H2 groupsas well as C13H2 and C15H2 groups of morpholin are also non-equivalent (Table 2, Fig. 3). We suggest that an intramolecularNH� � �Cl–Pt interaction keeps one amino-proton in proximity toCl. Moreover, rotation around the Pt–N bond in 7–12 does notoccur on the NMR timescale at the recorded temperature due tounfavorable repulsions between the amine and the allyl group inthe cis-configuration. These lead to the above mentioned non-equivalences.

For the 1H NMR spectra of the examined complexes, there aresome anomalies. First, the signal of H18 in 5, 6, 9 and 10 becomesbroadened. Second, the distance between the two 195Pt satellitesof H7a (3JPtH

7a ) in 7–13 is quite large (105–110 Hz), larger than thoseof 2JPtH

8 and 2JPtH9 . We suppose that as quinoline and 2-methyl-

quinoline are large ligands, their molecule plane needs to beperpendicular or inclined to the coordination plane of Pt(II), andas a consequence H18 in 5, 6, 9 and 10 falls into the magneticanisotropic effect-region of the donor–acceptor Pt(C8@C9) bond.

Fig. 4. Molecular structure of [PtCl(Meug-1H)(2-MePhNH2)] (14) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. Mostimportant bond lengths (Å) and angles (�): Pt1–C1 2.001(4), Pt1–C8 2.132(4), Pt1–C9 2.127(4), Pt1–N1 2.177(3), Pt1–Cl1 2.324(1), C8@C9 1.394(7), C1–Pt1–Cl1 93.96(11),C1–Pt1–C8 81.88(16), C1–Pt1–C9 87.06(16), N1–Pt1–C8 97.09(13), N1–Pt1–C9 91.91(15), N1–Pt1–Cl1 87.12(9).

Table 3The cell in vitro cytotoxicity of the examined compounds, IC50, lg/mL.

Cancer cell 1 3 4 5 6 9 11 12 13

KB 25.2 67.1 3.7 3.4 25.2 3.2 11.2 109.5 72.5MCF7 32.0 72.3 7.3 5.7 32.0 8.5 17.5 82.8 128.0

T.T. Da et al. / Polyhedron 85 (2015) 104–109 109

In 7–14 proton H7a also falls into another anisotropy-effect-regionof the donor–acceptor Pt(C8@C9) bond (as seen in Fig. 4).

The nine complexes were tested for cell in vitro cytotoxicity onhuman cancer cells KB and MCF7. The IC50 values are listed inTable 3. The complexes containing pyridine or quinoline, namely[PtCl2(Meug)(Pyridine)Cl] (4), [PtCl2(Meug)(Quinoline)] (5) and[PtCl(Meug-1H)(Quinoline)] (9), exhibit significant activities onhuman cancer cells KB and MCF7.

4. Conclusions

In this work, two series of platinum(II) complexes containingmethyleugenol (a natural aryl olefin), [PtCl2(Meug)(Amine)] (1–6)and chelating methyleugenol, [PtCl(Meug-1H)(Amine)] (7–13),were synthesized and their spectral (IR, 1H NMR, 13C NMR) andstructural properties were investigated. In complexes 1–6 methyl-eugenol coordinates with Pt(II) through the ethylenic double bondof the allyl group, and the amine is in a trans-position in compar-ison to the ethylenic double bond. In complexes 7–13 the chelatingmethyleugenol ligand is bound to Pt(II) both through the ethylenicdouble bond of the allyl group and via the aromatic carbon. NOESYspectra and single-crystal X-ray diffraction of [PtCl(Meug-1H)(o-toluidine)] (14) indicate that in 7–14 the amines are in a cis-posi-tion with respect to the ethylenic double bond. Some unusualstructural features of the examined complexes are explained.[PtCl2(Meug)(Pyridine)] (4), [PtCl2(Meug)(Quinoline)] (5) and[PtCl(Meug-1H)(Quinoline)] (9) exhibit strong activities on humancancer cells KB with IC50 values of 3.7, 3.4 and 3.2 lg/mL,respectively.

Acknowledgements

This research is funded by Vietnam National Foundation for Sci-ence and Technology Development (NAFOSTED) under grant num-ber 104.02-2012.66.

Appendix A. Supplementary data

CCDC 992331 contains the supplementary crystallographic datafor 14. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the CambridgeCrystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.

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