Accepted Manuscript

Cyclometalated rhodium(III) complexes bearing dithiocarbamate derivative:synthesis, characterization, interaction with DNA and biological study

Titas Mukherjee, Buddhadeb Sen, Animesh Patra, Snehasis Banerjee, GeetaHundal, Pabitra Chattopadhyay

PII: S0277-5387(13)00787-0DOI: http://dx.doi.org/10.1016/j.poly.2013.11.028Reference: POLY 10441

To appear in: Polyhedron

Received Date: 31 August 2013Accepted Date: 22 November 2013

Please cite this article as: T. Mukherjee, B. Sen, A. Patra, S. Banerjee, G. Hundal, P. Chattopadhyay, Cyclometalatedrhodium(III) complexes bearing dithiocarbamate derivative: synthesis, characterization, interaction with DNA andbiological study, Polyhedron (2013), doi: http://dx.doi.org/10.1016/j.poly.2013.11.028

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1

Cyclometalated rhodium(III) complexes bearing dithiocarbamate derivative: synthesis, 1

characterization, interaction with DNA and biological study 2

3

Titas Mukherjeea, Buddhadeb Sen,

a Animesh Patra,

a Snehasis Banerjee

b, Geeta Hundal

c, 4

Pabitra Chattopadhyaya* 5

aDepartment of Chemistry, Burdwan University, Golapbag, Burdwan-713104, India 6

bGovt. College Of Engineering and Leather Technology, Salt Lake Sector-III, Kolkata 98

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cDepartment of Chemistry, Guru Nanak Dev University, Amritsar-143005, India 8

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Abstract 11

Reaction of three different dithiocarbamates (4-MePipzcdtH, L1H; MorphcdtH, L2H and 4-12

BzPipercdtH, L3H) with [Rh(2-C6H4py)2Cl]2.1/4CH2Cl2 afforded a class of rhodium(III) 13

complexes of the type [RhIII(2-C6H4py)2(L)]. The complexes were fully characterized by several 14

spectroscopic tools along with a detailed structural characterization of [Rh(2-C6H4py)2(L1)] (1) 15

by single crystal X-ray diffraction. Structural analysis of 1 showed a distorted octahedron in 16

which both of the 2-phenylpyridyl nitrogens are in axial positions, trans to one another and the 17

sulfur atoms are opposite to the phenyl rings. Electrochemical analysis by cyclic voltammetry 18

reveals irreversible redox behavior of the rhodium centre in 1, 2 and 3. Their DNA binding 19

ability have been also evaluated from the absorption spectral study as well as fluorescence 20

quenching properties, suggesting the intercalative interaction of the complexes with CT-DNA 21

due to the stacking between the aromatic chromophore and the base pairs of DNA. Antibacterial 22

activity of complexes has also been studied by agar disc diffusion method against some species 23

2

of pathogenic bacteria (Escherichia coli, Vibrio cholerae, Streptococcus pneumonia and Bacillus 24

cereus). 25

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Keywords : Cyclometalated rhodium(III) complex; dithiocarbamates, crystal structure, DFT, 27

DNA binding, antimicrobial study 28

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*Corresponding author: E-mail: pabitracc@yahoo.com 31

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1. Introduction 47

Rhodium(III) complexes are the subject of current research activity in the interaction of 48

complexes with biomolecules as well as the rhodium catalyst is able to fulfill its role over the 49

other conventional catalysts due to the capability of the metal to change its coordination number 50

from six to four and also the oxidation state from Rh(III) to Rh(I). This change appears as a 51

chemically irreversible two-electron reduction involving ligand loss from octahedral Rh(III) to 52

form square planar Rh(I) complexes. Loss of the ligand depends on the nature of the ligands 53

present in mixed ligand systems which allow one to tune the electrochemical potential and affect 54

the reactivity of the rhodium metal center [1]. The discovery of the catalytic properties of 55

Wilkinson’s catalyst, viz. [RhCl(PPh3)3] naturally brought about a widespread search for other 56

rhodium phosphines with catalytic activity [2,3]. Further, octahedral diimine rhodium(III) 57

complexes are of interest as they have been used in the process of photochemical reduction of 58

H2O to H2 [4]. 59

The dithiocarbamates (R2NCS2-) have been considered as versatile ligands for bonding to 60

transition as well as main group metal ions [5-17], and got an enormous attention because of their 61

importance in several fields such as the chemical industry, biology and biochemistry [18-21]. The 62

nature of the heterocycle attached to dithiocarbamate fragment appears crucial so as to vary the 63

electron properties of these ligands and thus to control the potential pharmacological attributes as 64

well as the catalytic efficiency of the metal complexes [22]. Coordination complexes of 65

platinoids with dithiocarbamato ligands are known in the literature [9-13] and also palladium(II) 66

and platinum(II) complexes of dithiocarbamato groups together with mono- or diamine ligands 67

[14-17]. But to the best of our knowledge so far, report of rhodium(III) cyclometalated 68

complexes bearing dithiocarbamate derivative is still unexplored. 69

4

The binding interactions of these complexes with DNA have also been studied 70

systematically to explore the biological activity of the new complexes as we know the fact of the 71

activity of cisplatin by coordination to DNA [23,24]. And from thorough pharmacological 72

mechanistic studies it is also known that small molecules interact with DNA via electrostatic 73

forces, groove binding, or intercalation [25], and their effectiveness depends on the mode and 74

affinity of the binding [26]. Intercalation is one of the most important among these interactions. 75

Therefore, the search for drugs that show intercalative binding to DNA has been an active 76

research area for the past several decades [27]. Moreover, although rhodium metal is not bio-77

essential element but its compounds have useful applications in the biological field [28-31] and 78

have significant pharmacological effects through the interaction with DNA [32]. 79

Encouraged by the advantages of the facts stated above, we isolated a new series of 80

cyclometalated rhodium(III) complexes bearing dithiocarbamate derivatives by a high yield 81

synthetic pathway under mild reaction conditions. The present report deals with the chemistry of 82

these [RhIII(2-C6H4py)2(SS)] complexes, where SS = 4-MePipzcdtH, MorphcdtH, 4-BzPipercdtH 83

with special reference to their formation, structural characterization and electrochemical 84

behavior. The binding interactions of these complexes with calf thymus-DNA (CT-DNA) have 85

also been studied systematically to explore the mode of biological activity as part of our 86

continuing interest [12,33]. In addition, antibacterial activity of the complexes (1, 2 and 3) 87

against some pathogenic bacteria, namely Escherichia coli, Vibrio cholerae, Streptococcus 88

pneumonia and Bacillus cereus has also been studied by agar disc diffusion method. 89

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2. Experimental 94

2.1. Materials and physical measurements 95

Rhodium trichloride, 2-phenylpyridine (2-C6H4py), morpholine and 4-benzylpiperidine 96

(Aldrich) were purchased and used without further purification. [Rh(2-C6H4py)2Cl]2.1/4CH2Cl2 97

was prepared following the reported procedure [34]. 4-Methylpiperazine (Aldrich) has been dried 98

by refluxing over NaOH beads, the colorless liquid obtained after distillation and stored over 99

NaOH beads. Solvents used for spectroscopic studies and for synthesis were purified and dried 100

by standard procedures before used. The organic moieties, 4-methylpiperazine-l-carbodithioic 101

acid (4-MePipzcdtH, L1H), morpholine-4-carbodithioic acid (MorphcdtH, L

2H) and 4-benzyl- 102

piperidine-l-carbodithioic acid (4-BzPipercdtH, L3H) were obtained as solid products following 103

the reported procedure [12]. 104

The Fourier transform infrared spectra of the ligand and the complexes were recorded on a 105

Perkin-Elmer FTIR model RX1 spectrometer using KBr pellet in the range 4000 - 300 cm-1. The 106

solution phase electronic spectra were recorded on an JASCO UV–Vis/NIRspectrophotometer 107

model V-570 in the range 200-1100 nm. Elemental analyses were carried out on a Perkin-Elmer 108

2400 series-II CHNS Analyzer. The fluorescence spectra complex bound to DNA were obtained 109

at an excitation wavelength of 522 nm in the Fluorimeter (Hitachi-2000). Mass spectra of 1, 2 110

and 3 were recorded on Micromass Q-Tof microTM. NMR spectrum of the ligands and complexes 111

has been recorded on Bruker DPX-300. Solution conductivity and redox potentials were 112

measured using Systronics Conductivity Meter 304 model and CHI620D potentiometer in DMF 113

at complex concentration of ~10-3 mol L-1. Viscosity experiments were conducted on an 114

Ostwald’s viscometer, immersed in a thermostated water-bath maintained to 25oC. 115

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2.2. Syntheses of [Rh(2-C6H4py)2(L1)] (1) [Rh(2-C6H4py)2(L

2)] (2) and [Rh(2-C6H4py)2(L

3)] (3) 118

The complexes have been synthesized following a common procedure stated as below. The 119

ligand, L1H (89.4 mg, 0.508mmol) for complex 1, L2

H (83.8 mg, 0.508 mmol) for complex 2 or 120

L3H (127.0 mg, 0.508 mmol) for complex 3 was dissolved in DMSO-MeCN (v/v 1:1) solvent 121

mixture and to this ligand solution dropwise MeCN solution of [Rh(2-C6H4py)2Cl]2.1/4CH2Cl2 122

(468mg, 0.5mmol) was added. The mixture was then refluxed in nitrogen atmosphere for 12 h 123

and the color changed from faded yellow to orange. On slow evaporation of this solution orange 124

coloured microcrystalline solid appeared, which was purified by extracting the orange band in 125

column chromatography using MeCN as an eluant. Needle shaped crystals of [Rh(2-126

C6H4py)2(L1)] suitable for X-ray diffraction study were grown from this solution on evaporation 127

at ambient temperature. 128

Rh(2-C6H4py)2(L1)] (1): [C28H27N4RhS2]; Yield: 85 %. Anal. Calc.: C, 57.33; H, 4.64; N, 129

9.55; Anal. Found: C, 57.21; H, 4.58; N, 9.32; IR (cm-1): νC=N, 1495; νa(SCS), 1005, 996; ESI-MS 130

(m/z): [M+Na+], 609.576(25% abundance); [M+H+] 587.588 (69 % abundance). Conductivity 131

(Λo, M-1 cm-1) in DMF: 130 ; 1H NMR (δ, ppm in dmso-d6): 4.36 (m, 3H of N-CH3); 3.82 (m, 4H 132

of S2C-N(CH2)2); 3.20 (m, 4H of -N(CH2)2); protons of 2-C6H4py: C1(8.84, d, 2H), C2(7.27, m, 133

2H), C3(8.01, d, 2H), C4(7.69, d, 2H), C5(7.43, m, 2H), C6(7.68, d, 2H). 134

[Rh(2-C6H4py)2(L2)] (2): C27H24N3ORhS2; Yield: 80 %. Anal. Calc.: C, 56.54; H, 4.22; N, 135

7.33. Anal. Found: C, 56.52; H, 4.06 N, 7.29; IR (cm-1): νC=N, 1485; νa(SCS), 1030, 1014; ESI-MS 136

(m/z): [M+Na+], 596.528 (20 % abundance); [M+H+], 574.538 (64 % abundance). Conductivity 137

(Λo, M-1 cm-1) in DMF: 127. 1H NMR (δ, ppm in dmso-d6): 3.86 (m, 4H of S2C-N(CH2)2); 3.66 138

(m, 4H of O(CH2)2); protons of 2-C6H4py: C1(8.84, d, 2H), C2(7.27, m, 2H), C3(8.01, d, 2H), 139

C4(7.69, d, 2H), C5(7.43, m, 2H), C6(7.68, d, 2H). 140

7

[Rh(2-C6H4py)2(L3)] (3): C35H32N3RhS2; Yield: 73 %. Anal. Calc.: C, 63.53; H, 4.87; N, 141

6.35. Anal. Found: C, 63.44; H, 4.79; N, 6.02; IR (cm-1): νC=N, 1505; νa(SCS),1035, 1020; ESI-MS 142

(m/z): [M+Na+], 684.682 (18 % abundance); [M+H+], 662.688 (42 % abundance). Conductivity 143

(Λo, M-1 cm-1) in DMF: 132. 1H NMR (δ, ppm in dmso-d6): 7.29-7.32 (m, 5H of C6H5); 3.94 (m, 144

4H of S2C-N(CH2)2); 3.21 (t, 2H of CH2); 2.23 (m, 4H of CH2); protons of 2-C6H4py: C1(8.84, d, 145

2H), C2(7.27, m, 2H), C3(8.01, d, 2H), C4(7.69, d, 2H), C5(7.43, m, 2H), C6(7.68, d, 2H). 146

147

2.3. X-Ray crystallography 148

X-ray data of the suitable crystal of complex 1 were collected on a Bruker’s Apex-II CCD 149

diffractometer using MoKα (λ = 0.71069). The data were corrected for Lorentz and polarization 150

effects and empirical absorption corrections were applied using SADABS from Bruker. A total of 151

13691 reflections were measured out of which 4012 were independent and 2299 were observed 152

[I > 2σ(I)] for theta (θ) 32°. The structure was solved by direct methods using SIR-92 and refined 153

by full-matrix least squares refinement methods based on F2, using SHELX-97 [35]. The two fold 154

axis passes through the metal ion, nitrogens of the piprazine ring and their substituent carbon 155

atoms. Therefore the asymmetric unit contains half the molecule. All non-hydrogen atoms were 156

refined anisotropically. The refinement showed rotational disorder in the piprazine ring which 157

could be resolved by splitting the two unique carbon atoms into two components and refining 158

their sof and thermal parameters as free variables with restraints over the bond distances. All 159

hydrogen atoms were fixed geometrically with their Uiso values 1.2 times of the phenylene and 160

methylene carbons and 1.5 times of the methyl carbons. All calculations were performed using 161

Wingx package [36, 37]. Important crystallographic parameters are given in Table 1. 162

163

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2.4. Theoretical calculation 164

To clarify the configurations and energy level of the complexes 1, 2 and 3, DFT calculations 165

were carried out in G09W program using B3LYP/6-31G(d) calculation and correlation function 166

as implemented in the Gaussian program package Gaussian 09. Thermal contribution to the 167

energetic properties was considered at 298.15 K and one atmosphere pressure. 168

169

2.5. DNA binding experiments 170

All the experiments involving CT-DNA were studied by spectroelectronic titration and 171

fluorescence quenching technique by using ethidium bromide (EB) as a DNA scavenger and 172

performed the experiment as our previously standardized method [38]. 173

Tris–HCl buffer solution was used in all the experiments involving CT-DNA. This tris–HCl 174

buffer (pH 7.9) was prepared using deionized and sonicated HPLC grade water (Merck). The CT-175

DNA used in the experiments was sufficiently free from protein as the ratio of UV absorbance of 176

the solutions of DNA in tris–HCl at 260 and 280 nm (A260/A280) was almost ~1.9. The 177

concentration of DNA was determined with the help of the extinction coefficient of DNA 178

solution at 260 nm (ε260 of 6600 L mol-1 cm-1) [38]. Stock solution of DNA was always stored at 179

4 oC and used within four days. Concentrated stock solution of the complex 1 was prepared by 180

dissolving the compound in DMSO and suitably diluted with tris–HCl buffer to the required 181

concentration for all the experiments. Absorption spectral titration experiment was performed by 182

keeping constant the concentration of the complex 1 and varying the CT-DNA concentration. To 183

eliminate the absorbance of DNA itself, equal solution of CT-DNA was added both to the 184

complex 1 solution and to the reference solution. 185

In the ethidium bromide (EB) fluorescence displacement experiment, 5 µL of the EB tris–186

HCl solution (1.0 mmol.L-1) was added to 1.0 mL of DNA solution (at saturated binding levels), 187

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stored in the dark for 2.0 h. Then the solution of the compound was titrated into the DNA/EB 188

mixture and diluted in tris–HCl buffer to 5.0 mL to get the solution with the appropriate complex 189

1/CT-DNA mole ratio. Before measurements, the mixture was shaken up and incubated at room 190

temperature for 30 min. The fluorescence spectra of EB bound to DNA were obtained at an 191

excited wavelength of 522 nm in the Fluorimeter (Hitachi-2000). The interaction of the complex 192

1 with calf thymus DNA (CT-DNA) has been investigated by using absorption and emission 193

spectra. 194

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2.6. Antimicrobial screening 196

The biological activities of free dithiocarbamic acids and the rhodium(III) derivatives of 197

dithiocarbamates (1, 2 and 3) have been studied for their antibacterial activities by agar well 198

diffusion method [39-41]. The antibacterial activities were done at 100 µg/mL concentration of 199

different compounds in DMF solvent by using three pathogenic gram negative bacteria 200

(Escherichia coli, Vibrio cholerae, Streptococcus pneumoniae) and one gram positive pathogenic 201

bacteria (Bacillus cereus). DMF was used as a negative control. The Petri dishes were incubated 202

at 37 °C for 24 h. After incubation plates were observed for the growth of inhibition zones. The 203

diameter of the zone of inhibition was measured in mm. 204

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3. Results and Discussion 206

3.1. Synthesis and characterization of complexes 207

The bidentate sulphur ligands (L1H, L2

H, and L3H) were synthesized by the reaction between 208

carbon disulfide with different amines in ethanol, and later characterized by FTIR and 1H NMR. 209

Treatment of these ligands with [Rh(2-C6H4py)2Cl]2.1/4CH2Cl2 at refluxing condition in DMSO-210

MeCN (v/v 1:1) solvent mixture having nitrogen atmosphere resulted in cleavage of the chloro 211

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bridge and led to formation of mononuclear rhodium(III) complexes of general formula of 212

[RhIII(2-C6H4py)2(L)] which were obtained from the column chromatography using acetonitrile 213

as orange colored microcrystalline solid on evaporation. Here, the dithiocarbamates behaves as 214

bidentate monobasic ligands (see Scheme 1). The complexes (1-3) are sparingly soluble in 215

common organic solvents except hexane but fairly soluble in DMF and DMSO, and are stable in 216

both the solid state and solution in air. The molar conductivity of freshly prepared solution (~1 x 217

10-3 M concentration) of 1 (ΛM = 130 M-1 cm-1), 2 (ΛM = 127 M-1 cm-1) and 3 (ΛM = 132 M-1 218

cm-1) in DMF are fairly consistent with a non-electrolyte, respectively. The complexes are 219

diamagnetic in nature. The formulations of the complexes have been confirmed by spectroscopic 220

methods and elemental analyses. 221

222

3.2. Structural description of complex 1 223

An ORTEP view of the complex [Rh(2-C6H4py)2(L1)] (1) with atom labeling scheme is 224

illustrated in Fig.1, and a selection of bond distances and angles is listed in Table 2. The 225

structural analysis evidenced that the complex resides on a C 2/c site in the monoclinic crystal 226

system. The crystal structure of 1 shows a distorted octahedron in which both of the 2-227

phenylpyridyl nitrogens are in axial positions, trans to one another and the sulfur atoms are 228

opposite to the phenyl rings. As would be expected, both Rh-C σ-bonds are equal in length 229

(1.994(4) Å) and significantly shorter than the Rh-N dative bond lengths of 2.039(3) Å due to 230

the Rh-C σ-bonds increasing electron density on the metal center. The bond distance of Rh-C in 1 231

is comparable with the previously reported Rh-C bonds in cyclometalated complex (1.996(9) Å) 232

but the bond Rh-N is slightly longer than those (1.987(7) Å) [42], but both are comparable with 233

the reported values [43]. Both Rh–S distances are also equal in length (2.4854(11) Å), and these 234

11

are longer than those in [Rh(Et2NCS2)3] (2.364(3) Å) [44] due to trans influence of the strong σ-235

donating carbon atoms of the phenyl groups and shorter than those in similar type complex 236

[{Rh(Bu2-C6H4py)2}2{S2P(OMe)2}] (2.548(2) Å) due to attachment of sulphur atoms to carbon 237

to of more electronegativity than phosphorous, for this reason, the S-Rh-S angle of 71.00(5)o is 238

smaller compared to the observed value of 79.40(1)o in the previous report [43]. 239

240

3.3. IR Spectra 241

The IR spectrum of the ligands display an intense stretch at 2850 cm-1 and 1445-1430 cm-1 242

correspond to γC-H of N-Me and γC=N respectively. The γC-H of N-Me of L1H for 1 (2910cm-1) is blue 243

shifted than the γC-H of N-Me of the free ligand (2850 cm-1) indicating metal ligand coordination. 244

The band around 1590 cm-l indicates a double bond character of C-N bond in the ligand frame, 245

which is confirmed from the bond length of the X-ray structure. This fact could be attributed to 246

the electron releasing ability of the heterocyclic group towards the sulphur atoms, a feature that 247

induces an electron delocalization over the carbon-nitrogen bond and the CS2 fragment. This is 248

shown by the νC=N shift to higher energies (ca. 1510-1465 cm-l) with respect to the free acids (ca. 249

1445-1430 cm-1), and these bands lie in between the stretching frequencies expected for a double 250

C=N (1610-1690 cm-l) and single C-N bond (1250-1350 cm-1). The blue-shift of the C=N 251

stretching frequency on going from the free acids to their metal complexes gives support to the 252

typical bidentate character [45] of the carbodithioic acid ligands. Two bands in the region of 253

1040-965 cm-l (separated by less than 20 cm-l) assignable to the νa(SCS) and one band for the vs(SCS) 254

stretch in the region 705-675cm-l of the complexes suggest the unsymmetrical chelating bidentate 255

mode of coordination to rhodium(III) ion [46]. The stretchings due to νCOC (asym and sym), νN-Me 256

and νCCC (asym and sym) remain unchanged in the spectra of the complexes and in the free 257

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ligands. This observation helps to exclude any coordination to the metals via nitrogen and oxygen 258

donors. 259

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3.3 Electronic Spectra 261

The electronic spectra of 1, 2 and 3 in DMF were shown in Fig 2. The spectral data have 262

been tabulated in Table 3. Complexes 1, 2 and 3 display a lower energy band at 675nm, 672nm 263

and 675nm, respectively with low extinction coefficient values that correspond to the d–d 264

transition. The higher energy band at 360 nm for all three complexes with high extinction 265

coefficient values are due to the coordinated carbon atom from pipyridine moiety, C(σ)-Rh(III) 266

charge transfer (LMCT) transition. The other higher energy intense transitions at 374 nm and 360 267

nm are due to the n→π* and π→π* charge transfer transitions. 268

269

3.5. Redox studies 270

The cyclic voltammograms (CV) of the complexes 1, 2 and 3 were recorded in DMF solvent 271

at room temperature. Three electrode cell set up such as platinum, Ag/Ag+ (non-aquous) and a 272

platinum wire as a working, reference and auxiliary electrode respectively have been used for 273

measurements. The cyclic voltammograms of all the three complexes 1, 2 and 3 have been shown 274

in Fig. 3 and the electrochemical data have been tabulated in Table 4. The complexes exhibit an 275

irreversible reductive response at E1/2 value ≈ -0.697 V to -0.767 V versus Ag/Ag+ (non-aqueous) 276

corresponds to Rh3+/Rh+ couple. Small differences in the ∆Ep values 652 mV, 658mV, 654 mV 277

for 1, 2 and 3 respectively) have been observed that increases in the order 2> 3>1. This indicates 278

that the ease of reduction from Rh(III) to Rh(I) with respect to ligand electronic environment is 279

supposed to be much more in case of complex 1 and least in complex 2. The trend of reduction 280

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potential values followed can be explained by the availability of the electrons on the donor atoms 281

of the dithiocarbamate ligands. The electron donating capacity through σ bond of the six 282

membered heterocyclic ring increases in the order 2< 3<1 owing to the presence of different 283

substituents at the heteroatom i.e. highly electronegative O atom (2), -R effect of benzylic group 284

(3), +I effect of Me group (1) and so the trend of reduction potential followed as such, which is 285

further supported by theoretical calculation obtained from DFT study (viz. supporting 286

information). 287

288

3.6. DNA binding study of [Rh(2-C6H4py)2(L1)] 289

Absorption spectral study: Electronic absorption spectroscopy is an effective method to 290

examine the binding modes of complex 1 with DNA. In general, binding of the compound to the 291

DNA helix is testified by an increase of the CT band complex 1 due to the involvement of strong 292

intercalative interactions between an aromatic chromophore of compound and the base pairs of 293

DNA [47-49]. The absorption spectra of complex 1 in the absence and presence of CT-DNA is 294

given in Fig. 4. The extent of the hyperchromism in the absorption band is generally consistent 295

with the strength of intercalative binding/interaction [50,51]. Fig. 5 indicates that the complex 1 296

interacts strongly with CT-DNA (Kb = 1.54 x105 M-1), and the observed spectral changes may be 297

rationalized in terms of intercalative binding [52]. In order to further illustrate the binding 298

strength of the complex 1 with CT-DNA, the intrinsic binding constant Kb was determined from 299

the spectral titration data using the following equation [53]: 300

[DNA]/(εa–εf) = [DNA]/(εb–εf) + 1/[Kb (εb–εf)] (1) 301

where [DNA] is the concentration of DNA, εf, εa and εb correspond to the extinction coefficient, 302

respectively, for the free complex 1, for each addition of DNA to the complex 1 and for the 303

complex 1 in the fully bound form. A plot of [DNA]/(εa–εf) versus [DNA], gives Kb, the intrinsic 304

14

binding constant as the ratio of slope to the intercept. From the [DNA]/( εa–εf) versus [DNA] plot 305

(Fig. 5), the binding constant Kb for complex 1 was estimated to be 1.54 x 105 M-1 (R = 0.99746 306

for five points), indicating a strong binding of the complex 1 with CT-DNA. 307

Fluorescence quenching technique: Fluorescence intensity of EB bound to DNA at 612 308

nm shows a decreasing trend with the increasing concentration of the compound. The quenching 309

of EB bound to DNA by the compound is in agreement with the linear Stern–Volmer equation 310

[54]: 311

I0/I = 1 + Ksv [Q] (2) 312

where I0 and I represent the fluorescence intensities in the absence and presence of quencher, 313

respectively. Ksv is a linear Stern–Volmer quenching constant, Q is the concentration of 314

quencher. In the quenching plot in Fig. 7 of I0/I versus complex 1 Ksv value is given by the ratio 315

of the slope to intercept. The Ksv value for the complex 1 is 0.87 x 104 (R = 0.98873 for five 316

points), suggesting a strong affinity of 1 to CT-DNA. 317

Number of binding sites: Flurorescence quenching data were used to determine the binding 318

sites (n) for the compound 1 with CT-DNA. Fig. 6 shows the fluroscence spectra of EB-DNA in 319

the presence of different concentrations of compound 1. It can be seen that the fluroscence 320

intensity at 612 nm was used to estimate Ksv and n. 321

If it is assumed that there are similar and independent binding sites in EB-DNA, the 322

relationship between the fluroscence intensity and the quencher medium can be deduced from the 323

following Eq. (3): 324

nQ + B → Qn….B (3) 325

where B is the flurophore, Q is the quencher, [nQ + B] is the postulated complex between the 326

flurophore and n molecules of the quencher [47]. The constant K is given by Eq. (4): 327

K = [Qn….B]/[Q]n.[B] (4) 328

15

If the overall amount of biomolecules ( bound or unbound with the quencher) is Bo, then [Bo] = 329

[Qn…B]+ [B], where [B] is the concentration of unbound biomolecules, and the relationship 330

between the fluorescence intensity and the unbound biomolecule as [B]/[Bo] = I/Io , that is: 331

log[(Io-I)/I] = logK + nlog[Q] (5) 332

Where (n) is the number of binding site of compound complex 1 with CT-DNA, which can be 333

determined from the slope of log[(Io-I)/I] versus log[Q],as shown in the Fig. 8. The calculated 334

value of the number of binding sites (n) is 1.10 (R= 0.99869 for five points). The value of (n) 335

approximately equals 1, and thus indicates the existence of one binding site in DNA for 336

compound 1. 337

Viscosity Measurement: To further clarify the nature of interaction between complex 1 and 338

CT DNA, viscosity measurements were carried out. Upon binding, a DNA intercalator causes an 339

increase in the viscosity of the DNA double helix due to its insertion between the DNA base pairs 340

and consequently to the lengthening of the DNA double helix. In contrast, a partial and/or 341

nonclassical intercalation could bend (or kink) the DNA helix, reducing the effective length and 342

its viscosity [55]. The method is generally considered the least unambiguous to probe the mode 343

of binding of a compound to DNA. The effect of 1 on viscosity of CT DNA is shown in Fig. 9. 344

The viscosity of DNA increased dramatically upon addition of complex 1 and is nearly linear 345

(R2 = 0.99621 for nine points). These results strongly indicate that the complex 1 deeply into the 346

DNA base pairs in intercalative fashion. 347

348

3.7. Antibacterial activity 349

Antibacterial activity of the dithicarbamic acids (HL) and the corresponding complexes are 350

tabulated in Table 5. Comparisons of the biological activity of the dithicarbamates and their 351

rhodium(III) derivatives with the standard antibiotics, chloramphenicol at different 352

16

concentrations have been carried out taking usual precautions. From this study, it is inferred that 353

all the rhodium(III) complexes have higher activity than the ligand only, but little less efficient 354

than the antibiotics. The increased activity may be due to the increase of the delocalization of π-355

electrons over the whole chelate ring imparts the increased lipophilic character to the metal 356

complexes. This higher lipophilicity of the complexes facilitates the penetration ability with a 357

greater extent into the bacterial cell membranes, and as result it perturbs the respiration process of 358

the bacteria and diminish the further growth of the microorganisms. 359

360

4. Conclusion 361

Three complexes of diimine dithiocarbamate mixed ligand framework Rh(2-362

C6H4py)2(L1)](1), Rh(2-C6H4py)2(L

2)](2), Rh(2-C6H4py)2(L3)] (3) have been synthesized and 363

characterized by means of solid and solution phase spectroscopic studies including the X-ray 364

structure of 1. With the knowledge gained from the present study, attempts are now underway to 365

bind these ligands in the C,N,S-coordination fashion to iridium and other metal ions having 366

octahedral geometry. The present study of interaction with CT-DNA shows that these 367

cyclometalated rhodium(III) complexes having dithiocarbamate moieties are good intercalative 368

binding to with CT-DNA with an adequate number of coordination sites and this strongly binding 369

ability of the complexes as intercalator encourage to develop these materials as good anticancer 370

candidates. From the antibacterial studies it is found that all the metal complexes have higher 371

activities than the free dithiocarbamic acids (LH) against four pathogenic bacteria (Escherichia 372

coli, Vibrio cholerae, Streptococcus pneumonia and Bacillus cereus, among these three complex 373

2 has more antibacterial effect. 374

375

376

17

Supporting material 377

Crystallographic data for complex 1 have been deposited with the Cambridge Crystallographic 378

Data Centre, CCDC No. 932588. Copies of this information are available on request at free of 379

charge from CCDC, 12 Union Road, Cambridge, CB21EZ, UK (fax: +44-1223-336-033; e-mail: 380

deposit@ccdc.ac.uk or http://www.ccdc.cam.ac.uk). 381

382

Acknowledgements 383

Financial support from the Council of Scientific and Industrial Research (CSIR), New Delhi, 384

India is gratefully acknowledged. 385

386

387

388

389

References 390

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and refs. therein. 450

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[50] V.A. Bloomfield, D.M. Crothers, I. Tinoco, Physical Chemistry of Nucleic Acids, Harper 460

and Row, New York, 1974, p. 432. 461

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Chem. Soc. 111 (1989) 3051. 465

[54] O. Stern, M. Volmer, Z. Phys. 20 (1919) 183. 466

[55] S. Satyanarayana, J.C. Dabrowiak, J.B. Chaires, Biochemistry 31 (1992) 9319. 467

468

469

470

471

21

Figures’ Legend 472

Fig. 1. ORTEP view of the complex [Rh(2-C6H4py)2(L1)] (1) with atom labeling scheme 473

(excluded H for clarity). (Symmetry codes: (i) -x,y,z; (ii) x,-y,-z; (iii) -x,-y,-z). 474

Fig. 2. Electronic absorption spectra of 1, 2 and 3 in DMF 475

Fig. 3. Cyclic voltammograms (scan rate 50 mV/s) of 1, 2 and 3 in DMF solution of 0.1 M 476

TBAP, using platinum working electrode. 477

Fig. 4. Electronic spectral titration of complex 1 with CT-DNA at 267nm in tris-HCl buffer; 478

[Compound] = 1.09 x 10-4; [DNA]: (a) 0.0, (b) 1.25 x 10-6 , (c) 2.50 x 10-6 , (d) 3.75 x 10-6, 479

(e) 5.00 x 10-6 , (f) 6.25 x 10-6mol.L-1. Arrow indicates the increase of DNA concentration. 480

Fig. 5. Plot of [DNA]/(εa–εf) versus [DNA] for the absorption of CT-DNA with the complex 1 in 481

tris-HCl buffer 482

Fig. 6. Emission spectra of the CT-DNA-EB system in tris–HCl buffer upon the titration of the 483

compound complex 1. Kex = 522 nm; [EB] =0.96 x 10-4 molL-1; [DNA] = 9.9 x 10-6 molL-1; 484

[Compound]: (a) 0.0, (b) 1.36 x 10-5 , (c) 2.72 x 10-5 , (d) 4.08 x 10-5 , (e) 5.44 x 10-5 , 485

(f) 6.80 x 10-5molL-1 . Arrow indicates the increase of compound concentration. 486

Fig. 7. Emission spectra of the CT-DNA-EB system in Tris-HCl buffer upon titration with 487

complex 1c. λex = 522 nm; [EB] = 9.6×10-5 mol L-1, [DNA] = 1.25×10-5; [Complex]: (a) 0.0, 488

(b) 1.25×10-5, (c) 2.5×10-5 ,(d) 3.75×10-5, (e) 5.00×10-5, mol L-1. The arrow denotes the 489

gradual increase of complex concentration. Inset: plot of I0/I vs. [complex] of 1c; Ksv = 0.82 × 490

104 (R = 0.99965, n = 5 points). 491

Fig. 7. Plot of I0/I versus complex 1 for the titration of CT-DNA–EB system with complex 1 492

using spectrofluorimeter; linear Stern–Volmer quenching constant (Ksv) for complex 1 =0.87 493

x 104 ; (R = 0.98873 for five points). 494

22

Fig. 8. The linear plot shows log[(Io-I)/I] versus log[Q], where R = 0.99869 for five points 495

Fig. 9. Effect of increase of amount of 1 on the relative viscosity of CT DNA in tris-HCl having 496

50 mM NaCl buffer. 497

Scheme 1. Synthetic method of rhodium(III) complexes 498

23

Table 1. Crystallographic data for complex 1 499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

Empirical Formula C28 H27 N4 Rh S2

Identification code shelxl

Fw 586.59

Crystal system Monoclinic

Space group C 2/c

a, Å 16.683(5)

b, Å 17.840(4)

c, Å 10.251(5)

β, deg 126.223(5)

V, Å3 2461.3(15)

Z 4

Dcalcd. (g cm–3) 1.583

µ (MoKα), mm–1 0.889

F(000) 1200

θ range, deg 1.90 -31.84

No. of reflns collcd 13691

No. of independent reflns 4012

Rint 0.0544

No. of reflns (I > 2σ(I)) 2299

No. of refined paramaters 357

Goodness-of-fit (F2) 1.034

R1, wR2 (I >2σ(I)) [a] 0.0473, 0.1041

R indices (all data) R1 = 0.1053, .1342

24

Table 2. Coordination Bond lengths [Å] and angles [°] for complex 1 523

524

525

526

527

528

529

530

531

532

533

Symmetry transformations used to generate equivalent atoms: #1 -x+1, y, -z+3/2 534

535

536

Table 3. Electronic absorption spectral data 537

Compound λmax(nm) (10-5, ε/dm3 mol-1cm-1)a

1 360(7845), 374sh(6780), 385(6840),

675(160)

2 360(7900), 375sh(6680), 390(6700),

672(210)

3 360(7800), 382sh(6600), 390(6640),

675(200)

a in DMF solvent 538

Bond length (Å)

Rh(1) - C(11) 1.994(4) Rh(1) - C(11)#1 1.994(4)

Rh(1) - N(1) 2.039(3) Rh(1) - N(1)#1 2.039(3)

Rh(1) - S(1) 2.4854(11) Rh(1) - S(1)#1 2.4855(11)

Bond angle (o)

C(11)-Rh(1)-N(1) 80.30(13) C(11)#1-Rh(1)-N(1)#1 80.29(13)

C(11)-Rh(1)-N(1)#1 93.30(13) C(11)#1-Rh(1)-N(1) 93.30(13)

N(1)-Rh(1)-S(1) 170.86(11) N(1)-Rh(1)-N(1)#1 171.09(17)

C(11)-Rh(1)-S(1) 100.14(11) C(11)#1-Rh(1)-S(1)#1 100.15(11)

C (11)#1-Rh(1)-S(1) 90.15(9) N(1)#1-Rh(1)-S(1)#1 90.15(9)

N(1)#1-Rh(1)-S(1) 97.12(9) N(1)-Rh(1)-S(1)#1 97.11(9)

S(1)-Rh(1)-S(1)#1 71.00(5) C(11)-Rh(1)-C(11)#1 88.8(2)

25

Table 4. Electrochemical dataa for the complexes 1, 2 and 3. 539

Complex Epc(V) Epa(V) ∆Ep(mV) E1/2(V)

1 -1.023 -0.371 652 -0.697

2 -1.096 -0.438 658 -0.767

3 -1.077 -0.413 654 -0.744

aPotentials versus non-aqueous Ag/Ag+ reference electrode, scan rate 50 mV/s, supporting 540

electrolyte: tetra-N-butylammonium perchlorate (0.1 M). 541

542

543

Table 5. Antibacterial data of free dithiocarbamic acids (LH) and rhodium(III) complexes (1, 2 544

and 3) (100 µg/ ml) 545

Inhibition zone in mm Compound for Treatment

E. coli V.cholerae S.pneumoniae B. cereus

L1H 05 05 04 03

L2H 05 04 08 04

L3 04 07 06 03

1 11 14 17 06

2 16 17 20 08

3 12 14 18 07

Chloramphenicol 22 29 24 09

DMF 0 0 0 0

546

547

548

26

550

552

554

556

558

560

562

564

Fig. 1. ORTEP view of the complex [Rh(2-C6H4py)2(L1)] (1) with atom labeling scheme 565

(excluded H for clarity). (Symmetry codes: (i) -x,y,z; (ii) x,-y,-z; (iii) -x,-y,-z). 566

567

569

571

573

575

577

579

581

583

585

Fig. 2. Electronic absorption spectra of 1, 2 and 3 in DMF 586

587

588

350 400 450 5000

1

2

3

4

-----(3)

-----(1)

-----(2)

Ab

so

rba

nce

Wavelength(nm)

27

590

592

594

596

598

600

602

604

606

Fig. 3. Cyclic voltammograms (scan rate 50 mV/s) of 1, 2 and 3 in DMF solution with 0.1 M 607

TBAP, using platinum working electrode. 608

609

611

613

615

617

619

621

623

625

Fig. 4. Electronic spectral titration of complex 1 with CT-DNA at 267nm in tris-HCl buffer; 626

[Compound] = 1.09 x 10-4; [DNA]: (a) 0.0, (b) 1.25 x 10-6 , (c) 2.50 x 10-6 , (d) 3.75 x 10-6, 627

(e) 5.00 x 10-6 , (f) 6.25 x 10-6mol.L-1. Arrow indicates the increase of DNA concentration. 628

300 400 500 600 7000.0

0.1

0.2

0.3

0.4 f

a

Ab

s.

λλλλ(nm)

-1.5 -1.2 -0.9 -0.6 -0.3 0.0

-2

0

2

4

6

8

10

I ( µµ µµ

A)

E (V)

231

28

630

632

634

636

638

640

642

644

Fig. 5. Plot of [DNA]/(εa–εf) versus [DNA] for the absorption of CT-DNA with the complex 1 in 645

tris-HCl buffer 646

647

649

651

653

655

657

659

661

663

Fig. 6. Emission spectra of the CT-DNA-EB system in tris–HCl buffer upon the titration of the 664

compound complex 1. Kex = 522 nm; [EB] =0.96 x 10-4 molL-1; [DNA] = 9.9 x 10-6 molL-1; 665

[Compound]: (a) 0.0, (b) 1.36 x 10-5 , (c) 2.72 x 10-5 , (d) 4.08 x 10-5 , (e) 5.44 x 10-5 , (f) 666

6.80 x 10-5molL-1. Arrow indicates the increase of compound concentration. 667

668

1 2 3 4 5 6 7

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

[DN

A]/

( εε εεa- εε εε

f) x

10

10

6

560 600 640 680 720 760

200

400

600

800

1000

1200

Flu

res

ce

nc

e in

ten

sit

y (

a.u

.)

λλλλ (nm)

f

a

29

669

671

673

675

677

679

681

683

685

Fig. 7. Plot of I0/I versus complex 1 for the titration of CT-DNA–EB system with complex 1 686

using spectrofluorimeter; linear Stern–Volmer quenching constant (Ksv) for complex 1 = 687

0.87 x 104 ; (R = 0.98873 for five points). 688

689

691

693

695

697

699

701

703

705

Fig. 8. The linear plot shows log[(Io-I)/I] versus log[Q],where R = 0.99869 for five points 706

707

708

1 2 3 4 5 6 7 8 91.0

1.1

1.2

1.3

1.4

1.5

1.6

1.7

I / I o

[Complex 1] x 105

-4.0 -4.2 -4.4 -4.6 -4.8

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

log

[(I o

-I)/I]

log[Complex 1]

30

710

712

714

716

718

720

722

724

726

Fig. 9. Effect of increasing amount of 1 on the relative viscosity of CT DNA in tris-HCl, 50 mM 727

NaCl buffer (R2 = 0.99621 for nine points). 728

729

731

733

735

737

739

741

742

743

Scheme 1. Synthetic method of rhodium(III) complexes 744

745

746

747

0 2 4 6 8 10

1.00

1.04

1.08

1.12

1.16

(n/n

o)1

/3

[Complex 1]/[DNA]

LnH + [Rh(2-C6H4py)2Cl2]2 Reflux,12 h

DMSO-MeCN[Rh(2-C6H4py)2(Ln)]

n = 1, Complex 1n = 2, Complex 2n = 3, Complex 3

N

X

N

X= -N-CH3 , 4-MePipzcdtH (L1H)X= -O, MorphcdtH (L2H)

X= -CH-CH2Ph , 4-BzPipercdtH(L3H)

SH

S

2-C6H4py ppy

31

748

749

750

Graphical Abstract (Pictogram) 752

762

764

766

768

770

772

774

776

778

779

780

781

782

783

784

785

Rh(2-C6H4py)2(L1)] (1)

[Rh(2-C6H4py)2(L2)] (2)

[Rh(2-C6H4py)2(L3)] (3)

+ [Rh(2-C6H4py)2Cl2]2

X

N SH

S

32

786

787

788

789

790

791

792

793

Graphical Abstract (Synopsis) 794

Three new cyclometalated rhodium(III) complexes containing dithiocarbamate derivatives 795

(1, 2 and 3) have been synthesized and structurally characterized. Irreversible redox behavior of 796

the rhodium(III) centre in the complexes have been observed in the cyclic voltammetric 797

experiments. Study of interaction with DNA showed the strong intercalative binding nature of the 798

complexes with CT-DNA, and antibacterial study exhibited the complexes have higher activities 799

than the free dithiocarbamic acids (LH) against four pathogenic bacteria. 800

801

802

803