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Dinuclear metal phosphonates and -phosphates
Inorganica Chimica Acta 363 (2010) 2920–2928
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Dinuclear metal phosphonates and -phosphates Vadapalli Chandrasekhar *, Palani Sasikumar, Tapas Senapati, Atanu Dey Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e
i n f o
Article history: Received 30 December 2009 Received in revised form 9 March 2010 Accepted 16 March 2010 Available online 19 March 2010 Dedicated to Prof. Animesh Chakravorty on his 75th birthday Keywords: Phosphonates Phosphates Dinuclear complexes Plasmid cleavage Anti-ferromagnetism
a b s t r a c t The reaction of Cu(II) or Cd(II) salts with 2,4,6-iPr3C6H2PO3H2, 2,4,6-iPr3C6H2CH2PO3H2 or 2,6-iPr2C6H3OPO3H2 in the presence of strong chelating nitrogen ligands such as 2,20 -bipyridine (bpy), 1,10-phenanthroline (phen), 2-pyridylpyrazole (pypz) or 3,5-dimethyl pyrazole (dmpz) as the ancillary ligands afforded dinuclear copper or cadmium complexes [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2] (4), [Cu2(2, 6-iPr2C6H3OPO3H)2(bpy)2(OAc)2(CH3OH)2](CH3OH) (5), [Cd2(2,6-iPr2C6H3OPO3H)4 (bpy)2(CH3OH)2] 2(CH3OH) (6), [Cd2(2,6-iPr2C6H3OPO3H)4(phen)2] (7), [Cu2(2,6-iPr2C6H3OPO3H)2(PyPz)2(CH3OH)2] (8) and [Cu2(2,4,6-iPr3C6H2CH2PO3H)2(DMPz)2Cl2](CH3OH) (9) The molecular structures of 4–7 are grossly similar. The common structural features in these complexes are that the two metal centers are bridged by two bidentate [RPO2(OH)] ligands generating a central eight-membered ring. Each of the metal centers also contains a chelating nitrogen ligand and a monodentate phosphonate or a phosphate ligand. In 5 and 6 other terminal ancillary ligands are also present. In compound 8, each of the two copper centers contains a monodentate [RPO2(OH)] ligand along with a molecule of methanol. The two coppers are bridged by two monoanionic pyridylpyrazole ligands. The molecular structure of 9 is similar to that of 4–7. However, in 9 each of the two copper centers contain only terminal monodentate ligands in the form of two chlorides and a pyrazole. Magnetic studies on all of these copper complexes reveal an anti-ferromagnetic behavior at low temperatures. In addition, these complexes were found to be artificial nucleases and can convert supercoiled pBR322 DNA form I into nick form II in 1 min in the presence of an external oxidant through a hydrolytic and/or an oxidative pathway. Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction Transition metal phosphates, possessing extended structures are well-known [1–4]. The reaction of transition metal salts with sterically hindered phosphonic acids or organodihydrogen phosphates in conjunction with ancillary nitrogen ligands has been known to afford molecular complexes whose nuclearity can range from 2 to 16 [5–9]. Recently we were able to demonstrate that the use of chelating nitrogen ligands allows greater control over the resultant assembly. In this paper this theme is elaborated further and we demonstrate the efficacy of our three-components strategy (metal salt, phosphorus-based acid, and a chelating nitogen ligand) by a designed assembly of several dinuclear copper (II) and cadmium (II) complexes, [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2] (4), [Cu2(2,6-iPr2C6H3OPO3H)2(bpy)2 (OAc)2(CH3OH)2](CH3OH) (5), [Cd2(2,6-iPr2C6H3OPO3H)4(bpy)2(CH3OH)2]2(CH3OH) (6), [Cd2(2,6-iPr2C6H3OPO3H)4(phen)2] (7), [Cu2(2,6-iPr2C6H3OPO3H)2 (PyPz)2(CH3OH)2] (8) and [Cu2(2,4,6-iPr3C6H2CH2PO3H)2(DMPz)2Cl2](CH3OH) (9). In addition to determining the molecular structures of these complexes we have also studied their magnetic
* Corresponding author. E-mail address: [email protected] (V. Chandrasekhar). 0020-1693/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ica.2010.03.038
behavior as well as their utility as artificial nucleases. We also report the synthesis and structure of a new organophosphonic acid, 2,4,6-iPr3C6H2CH2PO3H2 (2).
2. Experimental 2.1. Materials and methods Cu(OAc)2H2O (Fluka, USA), CuCl2, 2,20 -bipyridine, 1,10-phenanthroline (Aldrich, USA), and Cd(OAc)22H2O (SD fine, India) were used as received. 2,4,6-tri-isopropylphenylphosphonic acid (1) and 2,6-di-isopropylphenyldihydrogenphosphate (3) were synthesized according to literature procedures [10]. Solvents were purified by using standard procedures [11]. Melting points were measured using a JSGW apparatus and are uncorrected. Elemental analyses were carried out by using a Thermo quest CE instrument model EA/110 CHNS-O elemental analyzer. IR spectra were recorded as KBr pellets on a Bruker Vector 22 FT IR spectrophotometer operating from 400 to 4000 cm1. 1H and 31P{1H} NMR spectra were recorded on a JEOL-JNM LAMBDA 400 model NMR spectrometer in CDCl3 and CD3OD solutions and the chemical shifts are referenced with respect to tetramethylsilane (1H) and 85% H3PO4 (31P), respectively. ESI-MS analyses were performed on a Waters
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Micromass Quattro Micro triple quadrupole mass spectrometer. Electro spray ionization (positive ion, full scan mode) was carried out using 100% methanol as the solvent and nitrogen gas for desolvation. Capillary voltage was maintained at 3 kV while the cone voltage was kept at 30 kV.
2.2. Synthesis 2.2.1. Synthesis of 2,4,6-tri-isopropylbenzylphosphonic acid, 2,4,6iPr3C6H2CH2P(O)(OH)2 (2) 2,4,6-tri-isopropylbenzyl chloride (9.86 g, 39,0 mmol and triethyl phosphite (13.0 g, 78.0 mmol) were heated under constant stirring in a nitrogen atmosphere at 140 °C for 12 h. Excess of triethyl phosphite and other volatiles were removed by heating at 100 °C in vacuo. The residue, mainly the diethylphosphonate ester was hydrolyzed by treating with Conc. HCl (60 mL) and heating the mixture under reflux for 12 h. Work up of this reaction mixture involved removing the excess of acid in vacuo, treatment of the residue with water (25 mL) followed again by the removal of the solvent in vacuo and finally treatment of the residue with CH3CN followed by a final removal of the solvent. This process afforded the phosphonic acid which was recrystallized from a solvent mixture of dimethylether and CH2Cl2 mixture (1:3) at room temperature. Yield: 6.9 g (59.2%) Mp: 180–182 °C. Anal. Calc. for C18H33O4P (344.41 amu): C, 62.77; H, 9.66. Found: C, 62.82; H, 9.73%. 1H NMR (400 MHz, CDCl3, d ppm) d 7.03 (s, 2H), 4.98 (s, 2H), 3.33 (septet, 2H), 3.1 (septet, 1H), 1.28 (d, 18H). 31P{1H} NMR (161.7 MHz, CDCl3, d ppm): 25.4 (s). ESI-MS (m/z): 299.2 (M+H, 100%). IR (CH2Cl2, m cm1): 3820 (s), 3722 (s), 3601 (w), 3535 (w), 2105 (m), 2055 (m), 1765 (w), 1712 (w), 1602 (s), 1571 (s), 1469 (s), 1301 (s), 1262 (vs), 963 (s). IR (KBr, mcm1): 3625–2780 (br), 2963 (vs), 2867 (vs), 2287 (m), 1609 (m), 1577 (m), 1463 (m), 1382 (m), 1361 (m), 1187 (s), 1004 (s), 930 (m), 877 (s), 789 (m), 668 (s), 582 (s).
2.3. General synthetic procedure used for the preparation of compounds 4–9 Stoichiometric amount of the metal (II) salt and the ancillary ligand was taken in distilled methanol and the resultant mixture was stirred for 5 min. At this stage a stoichiometric amount of the phosphorus acid was added to this reaction mixture all at once. This was allowed to stir at room temperature for 4 h. The volume of the solvent was reduced to 5 mL under vacuo, filtered and kept for crystallization at room temperature by slow evaporation. After about a week block-like crystals suitable for X-ray analysis were isolated. 2.3.1. [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2] (4) Quantities: Cu(CH3COO)2H2O (0.11 g, 0.55 mmol); 2,20 -bipyridine (0.09 g, 0.55 mmol); 2,4,6-iPr3C6H2PO3H2 (0.16 g, 0.55 mmol). Yield: 0.13 g (58.7% based on 2,4,6-iPr3C6H2PO3H2); Mp. 250 °C (d). Anal. Calc. for C80H112Cu2N4O12P4 (1572.70): C, 61.09; H, 7.18; N, 3.56. Found: C, 61.13; H, 7.21; N, 3.55%. IR (KBr, cm1): 1105 [s, (masym PO3)], 1046 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 1574.16 [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2+H]+, 1638.19 [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2(CH3OH)2+H]+. TGA, temperature ranges °C (weight loss %): 30–175 (10); 176–280 (12.7); 281–340 (41.1); 448–550 (6.5). 2.3.2. [Cu2(2,6-iPr2C6H3OPO3H)2(bpy)2(AcO)2(CH3OH)2]CH3OH (5) Quantities: Cu(CH3COO)2H2O (0.12 g, 0.60 mmol); 2,20 -bipyridine (0.09 g, 0.60 mmol); 2,6-iPr2C6H3OPO3H2 (0.16 g, 0.60 mmol). Yield: 0.32 g (89.6% based on 2,6-iPr2C6H3OPO3H2); Mp. 248– 249 °C. Anal. Calc. for C51H70Cu2N4O15P2 (1168.16): C, 52.44; H, 6.04; N, 4.80. Found: C, 52.56; H, 6.08; N, 4.78%. IR (KBr, cm1): 1089 [s, (masym PO3)], 1024 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 1074.01 [M2MeOH+H]+. TGA, temperature ranges °C (weight loss %): 30–140 (8.2); 181–380 (45); 471–545 (6.7); 546–765 (10.4).
Table 1 Crystal data and structure refinement parameters of 2–6. Identification code Empirical formula Formula weight Temperature (K) Crystal system, space group Unit cell dimensions a (Å) b (Å) c (Å) a (°) b (°) c (°) V (Å3) Z, calculated density (mg/m3) Absorption coefficient (mm1) F(0 0 0) Crystal size (mm) h Range for data collection (°) Index ranges
Reflections collected Independent reflections Completeness to h (%) Data/restraints/parameters Goodness-of-fit (GOF) on F2 Final R indices [I > 2r(I)] R indices (all data) Largest difference in peak and hole (e Å3)
2 C18H33O4P 344.41 100(2) triclinic, P-1
4 C80H112Cu2N4O12P4 1572.7 100(2) monoclinic, P2(1)/c
5 C51H66Cu2N4O15P2 1164.1 100(2) monoclinic, C2/c
6 C74H96Cd2N4O22P4 1742.23 100(2) monoclinic, P2(1)/n
8.043(5) 8.546(5) 15.274(5) 99.075(5) 96.017(5) 97.380(5) 1019.7(9) 2, 1.122 0.151 376 0.15 0.1 0.1 2.44–25.99 9 6 h 6 9, 9 6 k 6 10, 18 6 l 6 12 5800 3924 [Rint = 0.0229] 97.80 3924/0/208 1.025 R1 = 0.0618, wR2 = 0.1545 R1 = 0.0769, wR2 = 0.1656 0.665 and 0.525
10.6968(6) 14.1108(8) 26.4412(15) 90.000(5) 94.243(10) 90.000(5) 3980.1(4) 2, 1.312 0.676 1668 0.15 0.10 0.06 2.11–28.33 14 6 h 6 13, 18 6 k 6 18, 35 6 l 6 28 26 425 9871 [Rint = 0.0595] 99.3 9871/0/480 1.068 R1 = 0.0607, wR2 = 0.1251 R1 = 0.0826, wR2 = 0.1346 0.721 and 0.460
21.452(5) 13.284(5) 21.568(5) 90.000(5) 115.103(5) 90.000(5) 5566(3) 4, 1.389 0.889 2432 0.10 0.08 0.07 2.24–26.00 26 6 h 6 26, 16 6 k 6 13, 26 6 l 6 19 15 213 5439 [Rint = 0.0413] 98.9 5439/0/340 1.036 R1 = 0.0563, wR2 = 0.1525 R1 = 0.0715, wR2 = 0.1690 1.680 and 0.604
17.664(5) 11.198(5) 21.756(5) 90.000(5) 106.980(5) 90.000(5) 4116(2) 2, 1.406 0.666 1800 0.12 0.09 0.05 1.96–26.00 21 6 h 6 20, 13 6 k 6 12, 21 6 l 6 26 22 508 8051 [Rint = 0.0371] 99.5 8051/1/530 1.056 R1 = 0.0499, wR2 = 0.1240 R1 = 0.0614, wR2 = 0.1324 1.057 and 0.813
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Table 2 Crystal data and structure refinement parameters of 7–9. Identification code Empirical formula Formula weight Temperature (K) Crystal system, space group Unit cell dimensions a (Å) b (Å) c (Å) a (°) b (°) c (°) V (Å3) Z, calculated density (mg/m3) Absorption coefficient (mm1) F(0 0 0) Crystal size (mm) h Range for data collection Index ranges
Reflections collected Independent reflections Completeness to h (%) Data/restraints/parameters Goodness-of-fit (GOF) on F2 Final R indices [I > 2r(I)] R indices (all data) Largest diff. peak and hole
7 C72H88Cd2N4O16P4 1614.14 100(2) orthorhombic, Pbca
8 C42H56Cu2N6O10P2 993.95 100(2) triclinic, P 1
9 C42H68Cl2Cu2N4O6P2 1055.86 100(2) triclinic, P 1
12.5356(8) 20.4442(13) 28.4290(19) 90 90 90 7285.8(8) 4, 1.472 0.740 3328 0.11 0.06 0.04 2.04 to 26.00 ° 15 6 h 6 14, 23 6 k 6 25, 35 6 l 6 33 39 285 7146 [Rint = 0.0930] 99.8 7146/2/458 1.046 R1 = 0.0520, wR2 = 0.1150 R1 = 0.0801, wR2 = 0.1320 1.888 and 0.640 e.Å3
8.361(5) 11.328(5) 12.669(5) 102.502(5) 100.661(5) 90.956(5) 1149.2(10) 1, 1.436 1.056 518 0.10 0.05 0.03 2.20 to 26.00 ° 10 6 h 6 10, 9 6 k 6 13, 13 6 l 6 15 6478 4410 [Rint = 0.0381] 97.7 4410/2/288 1.014 R1 = 0.0604, wR2 = 0.1378 R1 = 0.0853, wR2 = 0.1638 0.993 and 0.483 e.Å3
8.334(5) 9.593(5) 15.733(5) 87.237(5) 85.411(5) 79.543(5) 1232.2(11) 2, 1.414 1.090 554 0.15 0.10 0.10 2.48 to 26.00 ° 10 6 h 6 10, 11 6 k 6 11, 14 6 l 6 19 7018 4717 [Rint = 0.0163] 97.4 4717/0/294 1.054 R1 = 0.0353, wR2 = 0.0867 R1 = 0.0396, wR2 = 0.0893 0.607 and 0.392 e.Å3
2.3.3. [Cd2(2,6-iPr2C6H3OPO3H)4(bpy)2(CH3OH)2]2CH3OH (6) Quantities: Cd(CH3COO)22H2O (0.13 g, 0.48 mmol); 2,20 -bipyridine (0.08 g, 0.48 mmol); 2,6-iPr2C6H3OPO3H2 (0.12 g, 0.48 mmol). Yield: 0.18 g (88.1% based on 2,6-iPr2C6H3OPO3H2); Mp. >260 °C (d). 31P{1H} NMR (CD3OD, d) 6.7 (s) and 5.6 (s). Anal. Calc. for C74H96Cd2N4O22P4 (1760.47): C, 50.55; H, 6.42; N, 3.19. Found: C, 51.57; H, 6.49; N, 3.15. IR (KBr, cm1): 1082 [s, (masym PO3)], 1020 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 1567.32 [M2MeOH+H]+. TGA, temperature ranges °C (weight loss %): 30–205 (6); 206– 375 (54.6.0); 435–500 (5.1); 501–750 (2.5).
2.3.6. [Cu2(2,4,6-iPr3C6H2CH2PO3H)2(DMPz)2Cl2]CH3OH (9) Quantities: CuCl2 (0.05 g, 0.37 mmol); 3,5-dimethylpyrazole (0.04 g, 0.37 mmol); 2,4,6-iPr3C6H2CH2PO3H2 (0.11 g, 0.37 mmol); 0.5 mL 1 M NaOH in water. Yield: 0.09 g (44.6% based on 2,4,6iPr3C6H2CH2PO3H2); Mp. >250 °C (d). Anal. Calc. for C42H68Cl2Cu2N4O6P2 (1055.86): C, 47.78; H, 6.49; N, 5.31. Found: C, 47.76; H, 6.48; N, 5.30%. IR (KBr, cm1): 1119 [s, (masym PO3)], 1008 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 1052.49 [MCl+MeOH]+. TGA, temperature ranges °C (weight loss %): 30–75 (3.3); 76.115 (6.1); 176.350 (29.6); 351–470 (21.7); 501–605 (13.4); 606–750 (7.2). 2.4. X-ray crystallography
2.3.4. [Cd2(2,6-iPr2C6H3OPO3H)4(phen)2] (7) Quantities: Cd(CH3COO)22H2O (0.11 g, 0.40 mmol); 1,10-phenanthroline (0.07 g, 0.40 mmol); 2,6-iPr2C6H3OPO3H2 (0.10 g, 0.40 mmol). Yield: 0.14 g (89.6% based on 2,6-iPr2C6H3OPO3H2); Mp. > 250 °C (d). 31P{1H} NMR (CD3OD, d) 6.9 (s) and 5.6 (s). Anal. Calc. for C72H88Cd2N4O16P4 (1614.20): C, 53.57; H, 5.49; N, 3.47. Found: C, 53.55; H, 5.49; N, 3.45. IR (KBr, cm1): 1092 [s, (masym PO3)], 1018 [s, (msymPO3)]. ESI-MS (CH3OH) m/z: 1615.32 [MH]+. TGA, temperature ranges °C (weight loss %): 30–220 (2.1); 221– 330 (39.1); 331–485 (9.9); 486–800 (6.7).
2.3.5. [Cu2(2,6-iPr2C6H3OPO3H)2(PyPz)2(CH3OH)2] (8) Quantities: Cu(CH3COO)2H2O (0.11 g, 0.53 mmol); 2-pyridylpyrazole (0.08 g, 0.53 mmol); 2,6-iPr2C6H3OPO3H2 (0.14 g, 0.53 mmol). Yield: 0.25 g (92.8% based on 2,6-iPr2C6H3OPO3H2); Mp. > 250 °C (d). Anal. Calc. for C42H56Cu2N6O10P2 (993.97): C, 50.75; H, 5.68; N, 8.46. Found: C, 50.73; H, 5.69; N, 8.45%. IR (KBr, cm1): 1082 [s, (masym PO3)], 1028 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 929.16 [M2MeOH+H]+. TGA, temperature ranges °C (weight loss %): 30–190 (2); 191–260 (21.8); 261–400 (24.3); 401–565 (7.4); 566–800 (14).
The crystal data for 2 and 4–9 are given in Tables 1 and 2. The data were collected on a Bruker Smart Diffractometer. Data were collected using a graphite-monochromated Mo Ka radiation (k = 0.71073 Å). All the structures were solved by direct methods using SHELXS-97 [12a] and refined by full-matrix least squares on F2 using SHELXL-97. All hydrogen atoms were included in idealized positions, and a riding model was used. Non-hydrogen atoms were refined with anisotropic displacement parameters. The crystallographic figures were generated by using DIAMOND 3.1f programme [12b]. 3. Results and discussion 3.1. Synthesis The new phosphonic acid, 2,4,6-iPr3C6H2CH2P(O)(OH)2 (2), was prepared according to Scheme 1. The first step involved the Arbuzov reaction between 2,4,6-tri-isopropylbenzyl chloride and triethyl phosphite to afford the corresponding diethylphosphonate ester. The latter was not isolated, but hydrolyzed further affording 2 in good yield (see Section 2). The 31P{1H} NMR spectrum of 2
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OEt P OEt
O Cl CH 2O, dryHCl CCl4, AcOH
O
P(OEt) 3
6% HCl
140 ºC
100 ºC
OH P OH
Scheme 1. Synthesis of 2,4,6-tri-isopropylbenzylphosphonic acid.
phosphonic acid or phosphate/2,20 -bipyridyl or 1,10-phenanthroline (Scheme 2). The strongly chelating ancillary ligand blocks two of the coordination sites on the metal ion and this together with the steric bulk of the phosphonic acid or the phosphate does not allow the cluster to grow. Using pyridylpyrazole as the ligand also leads to a dinuclear compound 8 albeit with a slight difference
showed a singlet at 25.4 ppm. ESI-MS spectra of 2 showed a parent ion peak (M+H, 100%) at m/z 299.2. The solid-state structure of 2 revealed it to be a dimer as a result of intermolecular hydrogen bonding (see vide infra). The dinuclear (Cu2 or Cd2) compounds 4–7 are formed in threecomponent reactions involving Cu(OAc)2H2O or Cd(OAc)22H2O/
R
M(OAc) 2 XH 2O + RPO3H2 +
N
MeOH
N
P
O
L
L1
O
OH
N
N
M
M
N
N
L1 O
HO
O
L
P R 4; M = Cu, R 5; M = Cu, R 6; M = Cd, R 7; M = Cd, R
= 2,4,6-iPr 3C6H2, N-N = bpy, L = 2,4,6-iPr 3C6H2PO3H -, L1 = nothing = 2,6-iPr 3C6H3O, N-N = bpy, L = CH3CO 2-, L1 = CH3OH = 2,6-iPr3C6H 3O, N-N = bpy, L = 2,6-iPr 3C6H3OPO 3H- , L1 = CH 3OH = 2,6-iPr3C6H 3O, N-N = phen, L = 2,6-iPr 3C6H 3OPO 3H-, L1 = nothing Scheme 2. Synthesis of 4–7.
R P
OH O
N
O
Cu(OAc)2 H2O + RPO3H2 + N N H
N
MeOH Stirr, 4h
N
N
L
Cu
Cu
L
N
N
R = 2,6-iPrC6H3O L = CH3OH
O
N
O
P R
HO
(8)
Scheme 3. Synthesis of 8.
R
CuCl 2 + RPO3H2 +
HN N
NaOH, MeOH Stirr, 4h
Cl
P
O
Cl
OH
O
R = 2,4,6-iPr 3C6H2CH2
O
HO
O P R (9)
Scheme 4. Synthesis of 9.
Cl
Cu
Cu N NH
HN N
Cl
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in the structure in that these multifunctional nitrogen ligands do not act as chelating ligands, instead they are involved in bridging the two copper centers (Scheme 3). The influence of the steric bulk of the phosphonic acid on the course of the final product is clearly seen in the reaction of CuCl2 with 2,4,6-iPr3C6H2CH2PO3H2 in the presence of 3,5-dimethylpyrazole. In this instance also a dinuclear compound (9) is formed (Scheme 4). ESI-MS studies on all the dinuclear complexes revealed the presence of prominent molecular ion peaks (see Supporting Information, Fig. S1). The diamagnetic compounds 6 and 7 show a pair of singlets (6.7 and 5.6 ppm for 6; 6.9 and 5.6 ppm for 7) consistent with their molecular structures (vide infra). 3.2. Molecular structures 3.2.1. Molecular structure of 2 The asymmetric unit of 2 (Fig. 1) contains one molecule of the phosphonic acid and one molecule of dimethyl ether. Selected bond parameters of 2 including those found in hydrogen bonding are given in Table S1. Two molecules of 2 form an O–HO hydrogen-bonded dimer, similar to that seen in many carboxylic acids [13], leading to the formation of an eight-membered non-planar ring (2P, 4O 2H). One of the P–OH units acts as a donor while the P@O group acts as an acceptor. The remaining OH group is not involved in hydrogen-bonding. The OO distance involved in this intermolecular hydrogen bonding interaction is 2.591 Å and the O–HO bond angle is 148.17° (see Supporting Information, Fig. S2, Table S1).
Fig. 2. Molecular structure of 4. Hydrogen atoms from aromatic ring and isopropyl group from phosphonic acid are omitted for clarity.
3.2.2. Molecular structures of the dinuclear complexes 4–9 The molecular structures of the dinuclear metal compounds 4– 7 are grossly similar and contain a central chair-shaped eightmembered M2P2O4 [M = Cu (4, 5) or Cd (6, 7)] inorganic ring [Figs. 2–5].The two metal atoms and the two phosphorus atoms lie in one plane and with respect to this a pair of oxygen atoms lie above while another pair is located below. In all these cases the bridging coordination of the singly deprotonated ligand [RP(O)2(OH)] can be considered as anisobidentate and the mode of coordination may be termed as 2.101 according to the Harris notation (Chart 1) [14].
Fig. 3. Molecular structure of 5. Hydrogen atoms from aromatic ring, methyl group, and isopropyl group from phosphate are omitted for clarity.
Fig. 1. Molecular structure of 2. Hydrogen atoms from methyl group and aromatic ring are omitted for clarity.
Each metal atom in 4–7 is bound by a chelating ligand (bpy in the case of 4, 5 and 6; phen in the case of 7). The other coordination environment around the metal atoms is slightly varied in each compound. In 4 each copper atom is bound by a monodentate [2,4,6-iPr3C6H2PO2OH] ligand leading to an overall coordination number of five and a coordination environment of 2N, 3O around each copper atom. The coordination geometry around the metal atoms in 4 may be described as distorted square pyramidal where the base of the pyramid consists of two oxygen and two nitrogen atoms, while the apical position is occupied by a third oxygen atom. In the case of 5 the two terminal copper atoms are six-coordinate (Fig. 3) due to the presence of terminal acetate and methanol ligands. The copper atoms in 6 on the other hand contain one monodentate [2,6-iPr2C6H3OPO3H] and a methanol molecule as terminal coordinating groups. In this case also the copper atoms are six-coordinate (2N, 4O). Finally, in 7 the two copper atoms
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Fig. 4. Molecular structure of 6. Hydrogen atoms from aromatic ring, methyl group and isopropyl group from phosphate are omitted for clarity. Fig. 6. Molecular structure of 8. Hydrogen atoms from methyl group, aromatic ring, pyrazole ring and isopropyl group from phosphate are omitted for clarity.
Fig. 5. Molecular structure of 7. Hydrogen atoms from aromatic ring and isopropyl group from phosphate are omitted for clarity.
Fig. 7. Molecular structure of 9. Hydrogen atoms from aromatic ring, methyl group and isopropyl group from phosphate are omitted for clarity.
are 5-coordinate (2N, 3O) and contain only one terminal monodentate [2,6-iPr2C6H3OPO3H] ligand each. The molecular structure of the dinuclear copper phosphate 8 is slightly different from those discussed above and consists of a sixmembered Cu2N4 inorganic ring. In this instance the 2-pyridylpy-
R
R
P
O M HO
O M
O
P
M HO
2.101 (a)
1.001 (b)
O
N
N M
N
M
2.111 (c)
R = 2,4,6-iPr3C 6H2, 2,6-iPr3C6H 3O M = Cu, Cd Chart 1. Coordination modes of phosphonate and 2-pyridyl pyrazole ligands found in 2–9.
Fig. 8. Complexes 4, 5, 8 and 9 (complex 4 corresponds to gel A, 5 gel B, 8 gel C and 9 gel D) mediated DNA cleavage experiment at different time intervals. Lane 1: DNA alone; lanes 2–5: DNA (pBR322) + complexes 4, 5, 8 and 9 (30, 60, 90 and 120 min, respectively).
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Fig. 9. pBR322 DNA cleavage by 4, 5, 8 and 9 in presence of MMPP (complex 4 corresponds to gel A, 5 to gel B, 8 to gel C and 9 to gel D) at different time intervals. Lane 1, DNA alone; lanes 2–5, DNA + complex + MMPP (at 1, 2, 3 and 4 min).
The molecular structure of 9 consists of an eight-membered chair-shaped Cu2P2O4 inorganic ring similar to that found in 4–7 (Fig. 7). All the metal and phosphorus atoms lie in one plane with respect to which the two oxygen atoms (O1 and O3*) are above the plane while the other two (O3 and O1*) are below the plane. The eight-membered Cu2P2O4 ring is formed as a result of an anisobidentate bridging coordination mode of the two [2,4,6iPr3C6H2CH2PO2OH] ligands. Each metal atom is further coordinated by terminal pyrazole and chloride ligands. The square pyramidal coordination environment around each copper atom consists of a basal plane comprising of two oxygen atoms, one nitrogen atom of the pyrazole ligand and one chloride ligand. The remaining chloride atom occupies the axial position. The Cu–Claxial bond is slightly longer (Table S7, Supporting Information). Magnetic susceptibility measurements for two representative compounds viz., 5 and 8 were carried out between 300 and 5 K. These studies (see Supporting Information) reveal that the room temperature (300 K) magnetic moments for 5 (1.46lB) and 8 (1.66lB) decrease to 1.28 (5) and 0.41 (8) lB at 5 K indicating an overall anti-ferromagnetic interaction between the two metal centers. We have not attempted to model the magnetic behavior. 3.3. Cleavage of plasmid DNA In view of the wide-spread interest in the use copper complexes in general and dinuclear copper complexes in particular as DNA cleavage reagents [15], we have systematically examined the DNA cleavage ability of the complexes 4, 5, 8 and 9 (Fig. 8). Time course experiments revealed that4, 5, 8 and 9 were able to mediate partial conversion (20–50%) of the supercoiled pBR322 DNA form I to nick form II in 2 h. To foster the reaction we have added magnesium monoperoxyphthalate (MMPP) and we observed a rapid conversion of the super coiled pBR322 DNA form I to form II within 1 min (Fig. 9). In the case of complexes 6 and 7 there is no nuclease activity, even in the presence of the external oxidant (see Supporting Information, Fig. S5).
Fig. 10. pBR322 Cleavage experiments involving 4, 5, 8 and 9 in presence of free radical scavengers and singlet oxygen quencher assisted by complex (complex 4 corresponds to gel A, 5 gel B, 8 gel C and 9 gel D) in a 2 min reaction. Lane 1, DNA alone; lane 2, pBR322 + complex + MMPP; lane 3, pBR322 + complex + MMPP + DMSO; lane 4, pBR322 + complex + MMPP + D-mannitol; lane 5, pBR322 + complex + MMPP + t-BuOH; lane 6, pBR322 + complex + MMPP + NaN3; lane 7, pBR322 + complex + MMPP + EDTA.
razole ligand bridges the two copper atoms through the pyrazole nitrogen atoms (N2 and N3, Fig. 6). In addition to the bridging coordination mode each pyridylpyrazole ligand also functions as a chelating ligand through one pyridine and one pyrazole nitrogen atoms to each of the copper atoms (Fig. 6). Additionally a mono anionic phosphate [2,6-iPr2C6H3OPO2OH] is present as a terminal ligand on each copper atom. A solvent methanol molecule completes the coordination environment around each copper (distorted square pyramidal, 3N, 2O). The coordination modes of the various ligands involved are summarized in Chart 1. The bond distance/angle data around copper are summarized in Table S6.
3.3.1. DNA cleavage mechanism Copper-based artificial nucleases function through oxidative and/or hydrolytic pathways. In view of this, we probed the cleavage mechanism of 4, 5, 8 and 9. In the presence of EDTA, the cleavage reaction is completely inhibited demonstrating a crucial role of copper for plasmid modification. Hydroxyl radical scavengers, dimethyl sulphoxide (DMSO), D-mannitol or tert-butylalcohol do not inhibit cleavage reactions demonstrating that radicals are not involved in the cleavage process. NaN3, a well-known quencher of singlet oxygen [16], inhibits the cleavage reaction in the case of 4, 5 and 9, which indicates that singlet oxygen may be involved in the cleavage process (Fig. 10). In contrast, in the case of complex 8, NaN3 does not inhibit the cleavage reaction, which demonstrates that singlet oxygen [16] is not involved in the cleavage process (see Fig. 10). However, hydrolytic pathway for plasmid modification also appears potent in the current instance as demonstrated by the fact that DNA cleavage does not decrease under anaerobic conditions
Fig. 11. pBR322 DNA cleavage in anaerobic conditions by 4, 5, 8 and 9 at 2 min time interval. Lane 1, DNA (pBR322) alone; lanes 2 and 3 for complex 4 + pBR322 + MMPP; lanes 4 and 5 for complex 5 + pBR322 + MMPP; lanes 6 and 7 for complex 8 + pBR322 + MMPP; lanes 8 and 9 for complex 9 + pBR322 + MMPP (lanes 2, 4, 6, 8 aerobic and 3, 5, 7, 9 for anaerobic condition).
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(Fig. 11). This cumulative circumstantial evidence points to the possibility of multiple reaction pathways in the plasmid cleavage activity mediated by 4, 5 and 9 where as exclusive hydrolytic pathway is indicated for complex 8. 4. Conclusion In conclusion we have prepared a series of dinuclear copper(II) and cadmium(II) phosphonates and -phosphates using a multicomponent synthetic strategy involving the metal salt, a nitrogen ancillary ligand and a phosphorus acid. Most of these compounds have similar structures containing a central M2P2O4 ring. In the case of 8, however, a central six-membered ring is formed as a result of the bridging mode of interaction of the pyridylpyrazole ligands. While the copper complexes are active nucleases, the cadmium complexes are not.
[5] [6]
Acknowledgment We thank the Department of Science and Technology, India and Council of Scientific and Industrial Research, India for financial support. V.C. is a Lalit Kapoor Chair Professor of Chemistry. V.C. is thankful for the Department of Science and Technology, for a J.C. Bose fellowship. P.S. and T.S. thanks Council of Scientific and Industrial Research, India for Senior Research Fellowship. A.D. thanks Council of Scientific and Industrial Research, India for Junior Research Fellowship. Appendix A. Supplementary material [7]
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Dinuclear metal phosphonates and -phosphates Vadapalli Chandrasekhar *, Palani Sasikumar, Tapas Senapati, Atanu Dey Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India
a r t i c l e
i n f o
Article history: Received 30 December 2009 Received in revised form 9 March 2010 Accepted 16 March 2010 Available online 19 March 2010 Dedicated to Prof. Animesh Chakravorty on his 75th birthday Keywords: Phosphonates Phosphates Dinuclear complexes Plasmid cleavage Anti-ferromagnetism
a b s t r a c t The reaction of Cu(II) or Cd(II) salts with 2,4,6-iPr3C6H2PO3H2, 2,4,6-iPr3C6H2CH2PO3H2 or 2,6-iPr2C6H3OPO3H2 in the presence of strong chelating nitrogen ligands such as 2,20 -bipyridine (bpy), 1,10-phenanthroline (phen), 2-pyridylpyrazole (pypz) or 3,5-dimethyl pyrazole (dmpz) as the ancillary ligands afforded dinuclear copper or cadmium complexes [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2] (4), [Cu2(2, 6-iPr2C6H3OPO3H)2(bpy)2(OAc)2(CH3OH)2](CH3OH) (5), [Cd2(2,6-iPr2C6H3OPO3H)4 (bpy)2(CH3OH)2] 2(CH3OH) (6), [Cd2(2,6-iPr2C6H3OPO3H)4(phen)2] (7), [Cu2(2,6-iPr2C6H3OPO3H)2(PyPz)2(CH3OH)2] (8) and [Cu2(2,4,6-iPr3C6H2CH2PO3H)2(DMPz)2Cl2](CH3OH) (9) The molecular structures of 4–7 are grossly similar. The common structural features in these complexes are that the two metal centers are bridged by two bidentate [RPO2(OH)] ligands generating a central eight-membered ring. Each of the metal centers also contains a chelating nitrogen ligand and a monodentate phosphonate or a phosphate ligand. In 5 and 6 other terminal ancillary ligands are also present. In compound 8, each of the two copper centers contains a monodentate [RPO2(OH)] ligand along with a molecule of methanol. The two coppers are bridged by two monoanionic pyridylpyrazole ligands. The molecular structure of 9 is similar to that of 4–7. However, in 9 each of the two copper centers contain only terminal monodentate ligands in the form of two chlorides and a pyrazole. Magnetic studies on all of these copper complexes reveal an anti-ferromagnetic behavior at low temperatures. In addition, these complexes were found to be artificial nucleases and can convert supercoiled pBR322 DNA form I into nick form II in 1 min in the presence of an external oxidant through a hydrolytic and/or an oxidative pathway. Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction Transition metal phosphates, possessing extended structures are well-known [1–4]. The reaction of transition metal salts with sterically hindered phosphonic acids or organodihydrogen phosphates in conjunction with ancillary nitrogen ligands has been known to afford molecular complexes whose nuclearity can range from 2 to 16 [5–9]. Recently we were able to demonstrate that the use of chelating nitrogen ligands allows greater control over the resultant assembly. In this paper this theme is elaborated further and we demonstrate the efficacy of our three-components strategy (metal salt, phosphorus-based acid, and a chelating nitogen ligand) by a designed assembly of several dinuclear copper (II) and cadmium (II) complexes, [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2] (4), [Cu2(2,6-iPr2C6H3OPO3H)2(bpy)2 (OAc)2(CH3OH)2](CH3OH) (5), [Cd2(2,6-iPr2C6H3OPO3H)4(bpy)2(CH3OH)2]2(CH3OH) (6), [Cd2(2,6-iPr2C6H3OPO3H)4(phen)2] (7), [Cu2(2,6-iPr2C6H3OPO3H)2 (PyPz)2(CH3OH)2] (8) and [Cu2(2,4,6-iPr3C6H2CH2PO3H)2(DMPz)2Cl2](CH3OH) (9). In addition to determining the molecular structures of these complexes we have also studied their magnetic
* Corresponding author. E-mail address: [email protected] (V. Chandrasekhar). 0020-1693/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ica.2010.03.038
behavior as well as their utility as artificial nucleases. We also report the synthesis and structure of a new organophosphonic acid, 2,4,6-iPr3C6H2CH2PO3H2 (2).
2. Experimental 2.1. Materials and methods Cu(OAc)2H2O (Fluka, USA), CuCl2, 2,20 -bipyridine, 1,10-phenanthroline (Aldrich, USA), and Cd(OAc)22H2O (SD fine, India) were used as received. 2,4,6-tri-isopropylphenylphosphonic acid (1) and 2,6-di-isopropylphenyldihydrogenphosphate (3) were synthesized according to literature procedures [10]. Solvents were purified by using standard procedures [11]. Melting points were measured using a JSGW apparatus and are uncorrected. Elemental analyses were carried out by using a Thermo quest CE instrument model EA/110 CHNS-O elemental analyzer. IR spectra were recorded as KBr pellets on a Bruker Vector 22 FT IR spectrophotometer operating from 400 to 4000 cm1. 1H and 31P{1H} NMR spectra were recorded on a JEOL-JNM LAMBDA 400 model NMR spectrometer in CDCl3 and CD3OD solutions and the chemical shifts are referenced with respect to tetramethylsilane (1H) and 85% H3PO4 (31P), respectively. ESI-MS analyses were performed on a Waters
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Micromass Quattro Micro triple quadrupole mass spectrometer. Electro spray ionization (positive ion, full scan mode) was carried out using 100% methanol as the solvent and nitrogen gas for desolvation. Capillary voltage was maintained at 3 kV while the cone voltage was kept at 30 kV.
2.2. Synthesis 2.2.1. Synthesis of 2,4,6-tri-isopropylbenzylphosphonic acid, 2,4,6iPr3C6H2CH2P(O)(OH)2 (2) 2,4,6-tri-isopropylbenzyl chloride (9.86 g, 39,0 mmol and triethyl phosphite (13.0 g, 78.0 mmol) were heated under constant stirring in a nitrogen atmosphere at 140 °C for 12 h. Excess of triethyl phosphite and other volatiles were removed by heating at 100 °C in vacuo. The residue, mainly the diethylphosphonate ester was hydrolyzed by treating with Conc. HCl (60 mL) and heating the mixture under reflux for 12 h. Work up of this reaction mixture involved removing the excess of acid in vacuo, treatment of the residue with water (25 mL) followed again by the removal of the solvent in vacuo and finally treatment of the residue with CH3CN followed by a final removal of the solvent. This process afforded the phosphonic acid which was recrystallized from a solvent mixture of dimethylether and CH2Cl2 mixture (1:3) at room temperature. Yield: 6.9 g (59.2%) Mp: 180–182 °C. Anal. Calc. for C18H33O4P (344.41 amu): C, 62.77; H, 9.66. Found: C, 62.82; H, 9.73%. 1H NMR (400 MHz, CDCl3, d ppm) d 7.03 (s, 2H), 4.98 (s, 2H), 3.33 (septet, 2H), 3.1 (septet, 1H), 1.28 (d, 18H). 31P{1H} NMR (161.7 MHz, CDCl3, d ppm): 25.4 (s). ESI-MS (m/z): 299.2 (M+H, 100%). IR (CH2Cl2, m cm1): 3820 (s), 3722 (s), 3601 (w), 3535 (w), 2105 (m), 2055 (m), 1765 (w), 1712 (w), 1602 (s), 1571 (s), 1469 (s), 1301 (s), 1262 (vs), 963 (s). IR (KBr, mcm1): 3625–2780 (br), 2963 (vs), 2867 (vs), 2287 (m), 1609 (m), 1577 (m), 1463 (m), 1382 (m), 1361 (m), 1187 (s), 1004 (s), 930 (m), 877 (s), 789 (m), 668 (s), 582 (s).
2.3. General synthetic procedure used for the preparation of compounds 4–9 Stoichiometric amount of the metal (II) salt and the ancillary ligand was taken in distilled methanol and the resultant mixture was stirred for 5 min. At this stage a stoichiometric amount of the phosphorus acid was added to this reaction mixture all at once. This was allowed to stir at room temperature for 4 h. The volume of the solvent was reduced to 5 mL under vacuo, filtered and kept for crystallization at room temperature by slow evaporation. After about a week block-like crystals suitable for X-ray analysis were isolated. 2.3.1. [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2] (4) Quantities: Cu(CH3COO)2H2O (0.11 g, 0.55 mmol); 2,20 -bipyridine (0.09 g, 0.55 mmol); 2,4,6-iPr3C6H2PO3H2 (0.16 g, 0.55 mmol). Yield: 0.13 g (58.7% based on 2,4,6-iPr3C6H2PO3H2); Mp. 250 °C (d). Anal. Calc. for C80H112Cu2N4O12P4 (1572.70): C, 61.09; H, 7.18; N, 3.56. Found: C, 61.13; H, 7.21; N, 3.55%. IR (KBr, cm1): 1105 [s, (masym PO3)], 1046 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 1574.16 [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2+H]+, 1638.19 [Cu2(2,4,6-iPr3C6H2PO3H)4(bpy)2(CH3OH)2+H]+. TGA, temperature ranges °C (weight loss %): 30–175 (10); 176–280 (12.7); 281–340 (41.1); 448–550 (6.5). 2.3.2. [Cu2(2,6-iPr2C6H3OPO3H)2(bpy)2(AcO)2(CH3OH)2]CH3OH (5) Quantities: Cu(CH3COO)2H2O (0.12 g, 0.60 mmol); 2,20 -bipyridine (0.09 g, 0.60 mmol); 2,6-iPr2C6H3OPO3H2 (0.16 g, 0.60 mmol). Yield: 0.32 g (89.6% based on 2,6-iPr2C6H3OPO3H2); Mp. 248– 249 °C. Anal. Calc. for C51H70Cu2N4O15P2 (1168.16): C, 52.44; H, 6.04; N, 4.80. Found: C, 52.56; H, 6.08; N, 4.78%. IR (KBr, cm1): 1089 [s, (masym PO3)], 1024 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 1074.01 [M2MeOH+H]+. TGA, temperature ranges °C (weight loss %): 30–140 (8.2); 181–380 (45); 471–545 (6.7); 546–765 (10.4).
Table 1 Crystal data and structure refinement parameters of 2–6. Identification code Empirical formula Formula weight Temperature (K) Crystal system, space group Unit cell dimensions a (Å) b (Å) c (Å) a (°) b (°) c (°) V (Å3) Z, calculated density (mg/m3) Absorption coefficient (mm1) F(0 0 0) Crystal size (mm) h Range for data collection (°) Index ranges
Reflections collected Independent reflections Completeness to h (%) Data/restraints/parameters Goodness-of-fit (GOF) on F2 Final R indices [I > 2r(I)] R indices (all data) Largest difference in peak and hole (e Å3)
2 C18H33O4P 344.41 100(2) triclinic, P-1
4 C80H112Cu2N4O12P4 1572.7 100(2) monoclinic, P2(1)/c
5 C51H66Cu2N4O15P2 1164.1 100(2) monoclinic, C2/c
6 C74H96Cd2N4O22P4 1742.23 100(2) monoclinic, P2(1)/n
8.043(5) 8.546(5) 15.274(5) 99.075(5) 96.017(5) 97.380(5) 1019.7(9) 2, 1.122 0.151 376 0.15 0.1 0.1 2.44–25.99 9 6 h 6 9, 9 6 k 6 10, 18 6 l 6 12 5800 3924 [Rint = 0.0229] 97.80 3924/0/208 1.025 R1 = 0.0618, wR2 = 0.1545 R1 = 0.0769, wR2 = 0.1656 0.665 and 0.525
10.6968(6) 14.1108(8) 26.4412(15) 90.000(5) 94.243(10) 90.000(5) 3980.1(4) 2, 1.312 0.676 1668 0.15 0.10 0.06 2.11–28.33 14 6 h 6 13, 18 6 k 6 18, 35 6 l 6 28 26 425 9871 [Rint = 0.0595] 99.3 9871/0/480 1.068 R1 = 0.0607, wR2 = 0.1251 R1 = 0.0826, wR2 = 0.1346 0.721 and 0.460
21.452(5) 13.284(5) 21.568(5) 90.000(5) 115.103(5) 90.000(5) 5566(3) 4, 1.389 0.889 2432 0.10 0.08 0.07 2.24–26.00 26 6 h 6 26, 16 6 k 6 13, 26 6 l 6 19 15 213 5439 [Rint = 0.0413] 98.9 5439/0/340 1.036 R1 = 0.0563, wR2 = 0.1525 R1 = 0.0715, wR2 = 0.1690 1.680 and 0.604
17.664(5) 11.198(5) 21.756(5) 90.000(5) 106.980(5) 90.000(5) 4116(2) 2, 1.406 0.666 1800 0.12 0.09 0.05 1.96–26.00 21 6 h 6 20, 13 6 k 6 12, 21 6 l 6 26 22 508 8051 [Rint = 0.0371] 99.5 8051/1/530 1.056 R1 = 0.0499, wR2 = 0.1240 R1 = 0.0614, wR2 = 0.1324 1.057 and 0.813
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Table 2 Crystal data and structure refinement parameters of 7–9. Identification code Empirical formula Formula weight Temperature (K) Crystal system, space group Unit cell dimensions a (Å) b (Å) c (Å) a (°) b (°) c (°) V (Å3) Z, calculated density (mg/m3) Absorption coefficient (mm1) F(0 0 0) Crystal size (mm) h Range for data collection Index ranges
Reflections collected Independent reflections Completeness to h (%) Data/restraints/parameters Goodness-of-fit (GOF) on F2 Final R indices [I > 2r(I)] R indices (all data) Largest diff. peak and hole
7 C72H88Cd2N4O16P4 1614.14 100(2) orthorhombic, Pbca
8 C42H56Cu2N6O10P2 993.95 100(2) triclinic, P 1
9 C42H68Cl2Cu2N4O6P2 1055.86 100(2) triclinic, P 1
12.5356(8) 20.4442(13) 28.4290(19) 90 90 90 7285.8(8) 4, 1.472 0.740 3328 0.11 0.06 0.04 2.04 to 26.00 ° 15 6 h 6 14, 23 6 k 6 25, 35 6 l 6 33 39 285 7146 [Rint = 0.0930] 99.8 7146/2/458 1.046 R1 = 0.0520, wR2 = 0.1150 R1 = 0.0801, wR2 = 0.1320 1.888 and 0.640 e.Å3
8.361(5) 11.328(5) 12.669(5) 102.502(5) 100.661(5) 90.956(5) 1149.2(10) 1, 1.436 1.056 518 0.10 0.05 0.03 2.20 to 26.00 ° 10 6 h 6 10, 9 6 k 6 13, 13 6 l 6 15 6478 4410 [Rint = 0.0381] 97.7 4410/2/288 1.014 R1 = 0.0604, wR2 = 0.1378 R1 = 0.0853, wR2 = 0.1638 0.993 and 0.483 e.Å3
8.334(5) 9.593(5) 15.733(5) 87.237(5) 85.411(5) 79.543(5) 1232.2(11) 2, 1.414 1.090 554 0.15 0.10 0.10 2.48 to 26.00 ° 10 6 h 6 10, 11 6 k 6 11, 14 6 l 6 19 7018 4717 [Rint = 0.0163] 97.4 4717/0/294 1.054 R1 = 0.0353, wR2 = 0.0867 R1 = 0.0396, wR2 = 0.0893 0.607 and 0.392 e.Å3
2.3.3. [Cd2(2,6-iPr2C6H3OPO3H)4(bpy)2(CH3OH)2]2CH3OH (6) Quantities: Cd(CH3COO)22H2O (0.13 g, 0.48 mmol); 2,20 -bipyridine (0.08 g, 0.48 mmol); 2,6-iPr2C6H3OPO3H2 (0.12 g, 0.48 mmol). Yield: 0.18 g (88.1% based on 2,6-iPr2C6H3OPO3H2); Mp. >260 °C (d). 31P{1H} NMR (CD3OD, d) 6.7 (s) and 5.6 (s). Anal. Calc. for C74H96Cd2N4O22P4 (1760.47): C, 50.55; H, 6.42; N, 3.19. Found: C, 51.57; H, 6.49; N, 3.15. IR (KBr, cm1): 1082 [s, (masym PO3)], 1020 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 1567.32 [M2MeOH+H]+. TGA, temperature ranges °C (weight loss %): 30–205 (6); 206– 375 (54.6.0); 435–500 (5.1); 501–750 (2.5).
2.3.6. [Cu2(2,4,6-iPr3C6H2CH2PO3H)2(DMPz)2Cl2]CH3OH (9) Quantities: CuCl2 (0.05 g, 0.37 mmol); 3,5-dimethylpyrazole (0.04 g, 0.37 mmol); 2,4,6-iPr3C6H2CH2PO3H2 (0.11 g, 0.37 mmol); 0.5 mL 1 M NaOH in water. Yield: 0.09 g (44.6% based on 2,4,6iPr3C6H2CH2PO3H2); Mp. >250 °C (d). Anal. Calc. for C42H68Cl2Cu2N4O6P2 (1055.86): C, 47.78; H, 6.49; N, 5.31. Found: C, 47.76; H, 6.48; N, 5.30%. IR (KBr, cm1): 1119 [s, (masym PO3)], 1008 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 1052.49 [MCl+MeOH]+. TGA, temperature ranges °C (weight loss %): 30–75 (3.3); 76.115 (6.1); 176.350 (29.6); 351–470 (21.7); 501–605 (13.4); 606–750 (7.2). 2.4. X-ray crystallography
2.3.4. [Cd2(2,6-iPr2C6H3OPO3H)4(phen)2] (7) Quantities: Cd(CH3COO)22H2O (0.11 g, 0.40 mmol); 1,10-phenanthroline (0.07 g, 0.40 mmol); 2,6-iPr2C6H3OPO3H2 (0.10 g, 0.40 mmol). Yield: 0.14 g (89.6% based on 2,6-iPr2C6H3OPO3H2); Mp. > 250 °C (d). 31P{1H} NMR (CD3OD, d) 6.9 (s) and 5.6 (s). Anal. Calc. for C72H88Cd2N4O16P4 (1614.20): C, 53.57; H, 5.49; N, 3.47. Found: C, 53.55; H, 5.49; N, 3.45. IR (KBr, cm1): 1092 [s, (masym PO3)], 1018 [s, (msymPO3)]. ESI-MS (CH3OH) m/z: 1615.32 [MH]+. TGA, temperature ranges °C (weight loss %): 30–220 (2.1); 221– 330 (39.1); 331–485 (9.9); 486–800 (6.7).
2.3.5. [Cu2(2,6-iPr2C6H3OPO3H)2(PyPz)2(CH3OH)2] (8) Quantities: Cu(CH3COO)2H2O (0.11 g, 0.53 mmol); 2-pyridylpyrazole (0.08 g, 0.53 mmol); 2,6-iPr2C6H3OPO3H2 (0.14 g, 0.53 mmol). Yield: 0.25 g (92.8% based on 2,6-iPr2C6H3OPO3H2); Mp. > 250 °C (d). Anal. Calc. for C42H56Cu2N6O10P2 (993.97): C, 50.75; H, 5.68; N, 8.46. Found: C, 50.73; H, 5.69; N, 8.45%. IR (KBr, cm1): 1082 [s, (masym PO3)], 1028 [s, (msym PO3)]. ESI-MS (CH3OH) m/z: 929.16 [M2MeOH+H]+. TGA, temperature ranges °C (weight loss %): 30–190 (2); 191–260 (21.8); 261–400 (24.3); 401–565 (7.4); 566–800 (14).
The crystal data for 2 and 4–9 are given in Tables 1 and 2. The data were collected on a Bruker Smart Diffractometer. Data were collected using a graphite-monochromated Mo Ka radiation (k = 0.71073 Å). All the structures were solved by direct methods using SHELXS-97 [12a] and refined by full-matrix least squares on F2 using SHELXL-97. All hydrogen atoms were included in idealized positions, and a riding model was used. Non-hydrogen atoms were refined with anisotropic displacement parameters. The crystallographic figures were generated by using DIAMOND 3.1f programme [12b]. 3. Results and discussion 3.1. Synthesis The new phosphonic acid, 2,4,6-iPr3C6H2CH2P(O)(OH)2 (2), was prepared according to Scheme 1. The first step involved the Arbuzov reaction between 2,4,6-tri-isopropylbenzyl chloride and triethyl phosphite to afford the corresponding diethylphosphonate ester. The latter was not isolated, but hydrolyzed further affording 2 in good yield (see Section 2). The 31P{1H} NMR spectrum of 2
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OEt P OEt
O Cl CH 2O, dryHCl CCl4, AcOH
O
P(OEt) 3
6% HCl
140 ºC
100 ºC
OH P OH
Scheme 1. Synthesis of 2,4,6-tri-isopropylbenzylphosphonic acid.
phosphonic acid or phosphate/2,20 -bipyridyl or 1,10-phenanthroline (Scheme 2). The strongly chelating ancillary ligand blocks two of the coordination sites on the metal ion and this together with the steric bulk of the phosphonic acid or the phosphate does not allow the cluster to grow. Using pyridylpyrazole as the ligand also leads to a dinuclear compound 8 albeit with a slight difference
showed a singlet at 25.4 ppm. ESI-MS spectra of 2 showed a parent ion peak (M+H, 100%) at m/z 299.2. The solid-state structure of 2 revealed it to be a dimer as a result of intermolecular hydrogen bonding (see vide infra). The dinuclear (Cu2 or Cd2) compounds 4–7 are formed in threecomponent reactions involving Cu(OAc)2H2O or Cd(OAc)22H2O/
R
M(OAc) 2 XH 2O + RPO3H2 +
N
MeOH
N
P
O
L
L1
O
OH
N
N
M
M
N
N
L1 O
HO
O
L
P R 4; M = Cu, R 5; M = Cu, R 6; M = Cd, R 7; M = Cd, R
= 2,4,6-iPr 3C6H2, N-N = bpy, L = 2,4,6-iPr 3C6H2PO3H -, L1 = nothing = 2,6-iPr 3C6H3O, N-N = bpy, L = CH3CO 2-, L1 = CH3OH = 2,6-iPr3C6H 3O, N-N = bpy, L = 2,6-iPr 3C6H3OPO 3H- , L1 = CH 3OH = 2,6-iPr3C6H 3O, N-N = phen, L = 2,6-iPr 3C6H 3OPO 3H-, L1 = nothing Scheme 2. Synthesis of 4–7.
R P
OH O
N
O
Cu(OAc)2 H2O + RPO3H2 + N N H
N
MeOH Stirr, 4h
N
N
L
Cu
Cu
L
N
N
R = 2,6-iPrC6H3O L = CH3OH
O
N
O
P R
HO
(8)
Scheme 3. Synthesis of 8.
R
CuCl 2 + RPO3H2 +
HN N
NaOH, MeOH Stirr, 4h
Cl
P
O
Cl
OH
O
R = 2,4,6-iPr 3C6H2CH2
O
HO
O P R (9)
Scheme 4. Synthesis of 9.
Cl
Cu
Cu N NH
HN N
Cl
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in the structure in that these multifunctional nitrogen ligands do not act as chelating ligands, instead they are involved in bridging the two copper centers (Scheme 3). The influence of the steric bulk of the phosphonic acid on the course of the final product is clearly seen in the reaction of CuCl2 with 2,4,6-iPr3C6H2CH2PO3H2 in the presence of 3,5-dimethylpyrazole. In this instance also a dinuclear compound (9) is formed (Scheme 4). ESI-MS studies on all the dinuclear complexes revealed the presence of prominent molecular ion peaks (see Supporting Information, Fig. S1). The diamagnetic compounds 6 and 7 show a pair of singlets (6.7 and 5.6 ppm for 6; 6.9 and 5.6 ppm for 7) consistent with their molecular structures (vide infra). 3.2. Molecular structures 3.2.1. Molecular structure of 2 The asymmetric unit of 2 (Fig. 1) contains one molecule of the phosphonic acid and one molecule of dimethyl ether. Selected bond parameters of 2 including those found in hydrogen bonding are given in Table S1. Two molecules of 2 form an O–HO hydrogen-bonded dimer, similar to that seen in many carboxylic acids [13], leading to the formation of an eight-membered non-planar ring (2P, 4O 2H). One of the P–OH units acts as a donor while the P@O group acts as an acceptor. The remaining OH group is not involved in hydrogen-bonding. The OO distance involved in this intermolecular hydrogen bonding interaction is 2.591 Å and the O–HO bond angle is 148.17° (see Supporting Information, Fig. S2, Table S1).
Fig. 2. Molecular structure of 4. Hydrogen atoms from aromatic ring and isopropyl group from phosphonic acid are omitted for clarity.
3.2.2. Molecular structures of the dinuclear complexes 4–9 The molecular structures of the dinuclear metal compounds 4– 7 are grossly similar and contain a central chair-shaped eightmembered M2P2O4 [M = Cu (4, 5) or Cd (6, 7)] inorganic ring [Figs. 2–5].The two metal atoms and the two phosphorus atoms lie in one plane and with respect to this a pair of oxygen atoms lie above while another pair is located below. In all these cases the bridging coordination of the singly deprotonated ligand [RP(O)2(OH)] can be considered as anisobidentate and the mode of coordination may be termed as 2.101 according to the Harris notation (Chart 1) [14].
Fig. 3. Molecular structure of 5. Hydrogen atoms from aromatic ring, methyl group, and isopropyl group from phosphate are omitted for clarity.
Fig. 1. Molecular structure of 2. Hydrogen atoms from methyl group and aromatic ring are omitted for clarity.
Each metal atom in 4–7 is bound by a chelating ligand (bpy in the case of 4, 5 and 6; phen in the case of 7). The other coordination environment around the metal atoms is slightly varied in each compound. In 4 each copper atom is bound by a monodentate [2,4,6-iPr3C6H2PO2OH] ligand leading to an overall coordination number of five and a coordination environment of 2N, 3O around each copper atom. The coordination geometry around the metal atoms in 4 may be described as distorted square pyramidal where the base of the pyramid consists of two oxygen and two nitrogen atoms, while the apical position is occupied by a third oxygen atom. In the case of 5 the two terminal copper atoms are six-coordinate (Fig. 3) due to the presence of terminal acetate and methanol ligands. The copper atoms in 6 on the other hand contain one monodentate [2,6-iPr2C6H3OPO3H] and a methanol molecule as terminal coordinating groups. In this case also the copper atoms are six-coordinate (2N, 4O). Finally, in 7 the two copper atoms
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Fig. 4. Molecular structure of 6. Hydrogen atoms from aromatic ring, methyl group and isopropyl group from phosphate are omitted for clarity. Fig. 6. Molecular structure of 8. Hydrogen atoms from methyl group, aromatic ring, pyrazole ring and isopropyl group from phosphate are omitted for clarity.
Fig. 5. Molecular structure of 7. Hydrogen atoms from aromatic ring and isopropyl group from phosphate are omitted for clarity.
Fig. 7. Molecular structure of 9. Hydrogen atoms from aromatic ring, methyl group and isopropyl group from phosphate are omitted for clarity.
are 5-coordinate (2N, 3O) and contain only one terminal monodentate [2,6-iPr2C6H3OPO3H] ligand each. The molecular structure of the dinuclear copper phosphate 8 is slightly different from those discussed above and consists of a sixmembered Cu2N4 inorganic ring. In this instance the 2-pyridylpy-
R
R
P
O M HO
O M
O
P
M HO
2.101 (a)
1.001 (b)
O
N
N M
N
M
2.111 (c)
R = 2,4,6-iPr3C 6H2, 2,6-iPr3C6H 3O M = Cu, Cd Chart 1. Coordination modes of phosphonate and 2-pyridyl pyrazole ligands found in 2–9.
Fig. 8. Complexes 4, 5, 8 and 9 (complex 4 corresponds to gel A, 5 gel B, 8 gel C and 9 gel D) mediated DNA cleavage experiment at different time intervals. Lane 1: DNA alone; lanes 2–5: DNA (pBR322) + complexes 4, 5, 8 and 9 (30, 60, 90 and 120 min, respectively).
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Fig. 9. pBR322 DNA cleavage by 4, 5, 8 and 9 in presence of MMPP (complex 4 corresponds to gel A, 5 to gel B, 8 to gel C and 9 to gel D) at different time intervals. Lane 1, DNA alone; lanes 2–5, DNA + complex + MMPP (at 1, 2, 3 and 4 min).
The molecular structure of 9 consists of an eight-membered chair-shaped Cu2P2O4 inorganic ring similar to that found in 4–7 (Fig. 7). All the metal and phosphorus atoms lie in one plane with respect to which the two oxygen atoms (O1 and O3*) are above the plane while the other two (O3 and O1*) are below the plane. The eight-membered Cu2P2O4 ring is formed as a result of an anisobidentate bridging coordination mode of the two [2,4,6iPr3C6H2CH2PO2OH] ligands. Each metal atom is further coordinated by terminal pyrazole and chloride ligands. The square pyramidal coordination environment around each copper atom consists of a basal plane comprising of two oxygen atoms, one nitrogen atom of the pyrazole ligand and one chloride ligand. The remaining chloride atom occupies the axial position. The Cu–Claxial bond is slightly longer (Table S7, Supporting Information). Magnetic susceptibility measurements for two representative compounds viz., 5 and 8 were carried out between 300 and 5 K. These studies (see Supporting Information) reveal that the room temperature (300 K) magnetic moments for 5 (1.46lB) and 8 (1.66lB) decrease to 1.28 (5) and 0.41 (8) lB at 5 K indicating an overall anti-ferromagnetic interaction between the two metal centers. We have not attempted to model the magnetic behavior. 3.3. Cleavage of plasmid DNA In view of the wide-spread interest in the use copper complexes in general and dinuclear copper complexes in particular as DNA cleavage reagents [15], we have systematically examined the DNA cleavage ability of the complexes 4, 5, 8 and 9 (Fig. 8). Time course experiments revealed that4, 5, 8 and 9 were able to mediate partial conversion (20–50%) of the supercoiled pBR322 DNA form I to nick form II in 2 h. To foster the reaction we have added magnesium monoperoxyphthalate (MMPP) and we observed a rapid conversion of the super coiled pBR322 DNA form I to form II within 1 min (Fig. 9). In the case of complexes 6 and 7 there is no nuclease activity, even in the presence of the external oxidant (see Supporting Information, Fig. S5).
Fig. 10. pBR322 Cleavage experiments involving 4, 5, 8 and 9 in presence of free radical scavengers and singlet oxygen quencher assisted by complex (complex 4 corresponds to gel A, 5 gel B, 8 gel C and 9 gel D) in a 2 min reaction. Lane 1, DNA alone; lane 2, pBR322 + complex + MMPP; lane 3, pBR322 + complex + MMPP + DMSO; lane 4, pBR322 + complex + MMPP + D-mannitol; lane 5, pBR322 + complex + MMPP + t-BuOH; lane 6, pBR322 + complex + MMPP + NaN3; lane 7, pBR322 + complex + MMPP + EDTA.
razole ligand bridges the two copper atoms through the pyrazole nitrogen atoms (N2 and N3, Fig. 6). In addition to the bridging coordination mode each pyridylpyrazole ligand also functions as a chelating ligand through one pyridine and one pyrazole nitrogen atoms to each of the copper atoms (Fig. 6). Additionally a mono anionic phosphate [2,6-iPr2C6H3OPO2OH] is present as a terminal ligand on each copper atom. A solvent methanol molecule completes the coordination environment around each copper (distorted square pyramidal, 3N, 2O). The coordination modes of the various ligands involved are summarized in Chart 1. The bond distance/angle data around copper are summarized in Table S6.
3.3.1. DNA cleavage mechanism Copper-based artificial nucleases function through oxidative and/or hydrolytic pathways. In view of this, we probed the cleavage mechanism of 4, 5, 8 and 9. In the presence of EDTA, the cleavage reaction is completely inhibited demonstrating a crucial role of copper for plasmid modification. Hydroxyl radical scavengers, dimethyl sulphoxide (DMSO), D-mannitol or tert-butylalcohol do not inhibit cleavage reactions demonstrating that radicals are not involved in the cleavage process. NaN3, a well-known quencher of singlet oxygen [16], inhibits the cleavage reaction in the case of 4, 5 and 9, which indicates that singlet oxygen may be involved in the cleavage process (Fig. 10). In contrast, in the case of complex 8, NaN3 does not inhibit the cleavage reaction, which demonstrates that singlet oxygen [16] is not involved in the cleavage process (see Fig. 10). However, hydrolytic pathway for plasmid modification also appears potent in the current instance as demonstrated by the fact that DNA cleavage does not decrease under anaerobic conditions
Fig. 11. pBR322 DNA cleavage in anaerobic conditions by 4, 5, 8 and 9 at 2 min time interval. Lane 1, DNA (pBR322) alone; lanes 2 and 3 for complex 4 + pBR322 + MMPP; lanes 4 and 5 for complex 5 + pBR322 + MMPP; lanes 6 and 7 for complex 8 + pBR322 + MMPP; lanes 8 and 9 for complex 9 + pBR322 + MMPP (lanes 2, 4, 6, 8 aerobic and 3, 5, 7, 9 for anaerobic condition).
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(Fig. 11). This cumulative circumstantial evidence points to the possibility of multiple reaction pathways in the plasmid cleavage activity mediated by 4, 5 and 9 where as exclusive hydrolytic pathway is indicated for complex 8. 4. Conclusion In conclusion we have prepared a series of dinuclear copper(II) and cadmium(II) phosphonates and -phosphates using a multicomponent synthetic strategy involving the metal salt, a nitrogen ancillary ligand and a phosphorus acid. Most of these compounds have similar structures containing a central M2P2O4 ring. In the case of 8, however, a central six-membered ring is formed as a result of the bridging mode of interaction of the pyridylpyrazole ligands. While the copper complexes are active nucleases, the cadmium complexes are not.
[5] [6]
Acknowledgment We thank the Department of Science and Technology, India and Council of Scientific and Industrial Research, India for financial support. V.C. is a Lalit Kapoor Chair Professor of Chemistry. V.C. is thankful for the Department of Science and Technology, for a J.C. Bose fellowship. P.S. and T.S. thanks Council of Scientific and Industrial Research, India for Senior Research Fellowship. A.D. thanks Council of Scientific and Industrial Research, India for Junior Research Fellowship. Appendix A. Supplementary material [7]
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