**Quantum Chemical Calculations for some Isatin Thiosemicarbazones**

Fatma Kandemirli\*,\*\* et al. *Niğde University, Turkey* 

## **1. Introduction**

Derivatives of isatin are reported to be present in mammalian tissues and body fluids (Casas et al., 1996; Agrawal & Sartorelli, 1978; Casas et al., 1994; Medvedev et al., 1998; Boon, 1997; Pandeya & Dimmock, 1993; Rodríguez-Argüelles et al., 1999; Casas et al., 2000) and possess antibacterial (Daisley & Shah, 1984), antifungal (Piscopo et al., 1987), and anti-HIV (Pandeya et al., 1998, 1999) activities. *N*-methylisatin--4', 4' – diethylthiosemicarbazone were also reported to have activity against the viruses such as cytomegalo and moloney leukemia viruses (Sherman et al., 1980; Ronen et al., 1987). With the help of combinatorial method, the cytotoxicity and antiviral activities of isaitin--thiosemicarbazones against the vaccine virus and cowpox virus-infected human cells were evaluated (Pirrung et al., 2005).

Some 5-fluoroisatin, 5-fluoro-1-morpholino/piperidinomethyl, and 5-nitroisaitn synthesized. They are reported to have anti-TB activity. ETM Study has also been carried out on these compounds (Karali et al., 2007). Synthesis and quantum chemical calculations of 5-methoxyisatin-3-(N-cyclohexyl), its Zn (II) and Ni (II) complexes (Kandemirli et al., 2009a), and 5-methoxyisatin-3-(*N*-cyclohexyl)thiosemicarbazone (Kandemirli et al., 2009b) were studied. The thiosemicarbazones likely possess anti-HIV activity according to 3D pharmacophoric distance map analysis (Bal et al., 2005).

Isatin-thiosemicarbazones may coordinate through the deprotonated nitrogen atom, sulphur atom of thiosemicarbazone group, and carbonyl oxygen atom with the metal, depending on its nature. Zinc (II) and mercury (II) complexes of isatin-3-thiosemicarbazones were reported to be coordinated through imino nitrogen and thiolato sulfur atoms and was suggested to have tetrahedral structures (Akinchan et al., 2002).

It was reported that only amino nitrogen atom coordinates in the Cu (II) complex (Ivanov et al., 1988). Quantum chemical calculations and IR studies on Zn (II) and Ni (II) complexes of

Taner Arslan5, Ayşe Erbay6 and Baybars Köksoy6

<sup>\*</sup> M. Iqbal Choudhary2, Sadia Siddiq2, Murat Saracoglu3, Hakan Sayiner4,

*<sup>2</sup>University of Karachi, Pakistan*, *3Erciyes University, Turkey*, *4Kahta State Hospital*, *Turkey*, *5Osmangazi University, Turkey*, *Turkey*, *6Kocaeli University, Turkey* 

*<sup>\*\*</sup>*Corresponding Author

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 27

Elemental analyses were performed by using a LECO CHN Elemental Analyzer. IR Spectra were recorded by Shimadzu FT-IR 8201 spectrometer with the KBr technique in the region of 4000-300 cm-1, which was calibrated by polystyrene. There was no decomposition of the samples due to the effect of potassium bromide. The 1H-NMR spectra were recorded in

The ligands under study were obtained by refluxing an ethanolic solution of 4-cyclohexyl-3 thiosemicarbazide, 4-benzyl-3-thiosemicarbazide, 4-phenyl-3-thiosemicarbazide, and 4-(4 chlorophenyl)-3-thiosemicarbazide with isatin (1H-indole-2,3-dione) or 5-methoxyisatin (all were purchased from Aldrich Chemical Company USA and used without purification), as

1 mmol of appropriate ligand was dissolved in 20 mL of ethanol at 50-55 ºC and then slowly added to ethanol solution (10 mL) of 0.5 mmol zinc acetate dihydrate or nickel acetate tetrahydrate. The mixture was refluxed for 2 h for nickel complex, and 6 h for zinc complex at approximately 75 oC. The zinc complex precipated at the end of the reflux, while the nickel complex precipated only after two days of stirring. The solid was filtered, washed

1H-NMR (DMSO-*d6*, ppm): 1-2 (cyclohexyl C-H), 4.11 (m, cyclohexyl C-H), 6.90-8.3

Calculated: % C: 53.92, % H: 5.128, % N: 16.77, % S: 9.60, found: % C: 53.49, % H: 5.644, % N:

1H-NMR (DMSO-*d6*, ppm): 3.35 (s, CH3-methoxy), 6.91-7.72 (aromatic C-H), 10.76 (s, NH),

Calculated: % C: 53.67, % H: 3.66, % N: 15.64, % S: 8.95, found: % C: 53.64, % H: 3.65, % N:

1H-NMR (DMSO- *d6*, ppm): 7.01-8.11 (aromatic C-H), 10.68 (s, NH), 11.01 (s, indole-NH)

described in the literature (Karali et al., 2007; Kandemirli et al., 2009a, 2009b**).**

DMSO-*d6* on a BRUKER DPX-400 (400 MHz) spectrometer.

**2.1 General procedure for synthesis of Ni and Zn complexes** 

with ethanol, and diethyl ether, and dried under vacuum.

(aromatic C-H), 8.95 (d, *J*= 7.8 Hz), NH 10.80 (s, indole-NH)

IR (cm-1): 1688 (C=O), 1595 (C=N), 819 (C=S)

IR (cm-1): 1697 (C=O), 1589 (C=N), 817 (C=S)

**2. Experimental** 

**2.1.1 [Zn(HICHT)2] (6)** 

16.06, % S: 9.58.

**2.1.2 [Zn(HMIPT)2] (8)** 

11.04 (s, indole-NH)

15.67, % S: 9.08.

**2.1.3 [Zn(HIPT)2] (9)** 

Yield: (90%). (M.p.: 310 ºC)

Yield: (64%). (M.p.: 320 ºC)

Yield: (80%). (M.p.: 288-290 ºC)

5-fluoro-isatin -3-(*N*-benzylthiosemicarbazone) have recently been reported (Gunesdogdu-Sagdinc et al., 2009).

During the current study, we prepared [Zn(HICHT)2], [Zn(HMIPT)2], [Zn(HIPT)2], [Zn(HICPT)2], [Zn(HIBT)2], [Ni(HMIPT)2], [Ni(HIPT)2], [Ni(HICPT)2], [Ni(HIBT)2], and [Ni(HICHT)2] derivatives, and characterized them with elemental analysis, and IR, UV, and 1H-NMR spectroscopic techniques.

In view of the reports about antimicrobial and antifungal activities of the isatin derivatives, we synthesized and screened compounds **1-16** (Table 1) for their antimicrobial effects in vitro against Bacillus subtilis, Escherichia coli, Stahpylococcus aureus, Shigella flexnari, Pseudomonas aeruginosa, and Salmonella typhi bacterial strains and Aspergillus flavus, Candida albicans, Microsporum canis, Fusarium solani, and Candida glabrata fungal strains. Compounds **1**, **14**, and **16** were found to be moderately active, compounds **2**, and **4** possess a good activity, while compound **13** exhibited a significant activity against Microsporum canis. Compounds **13**, **12**, and **4** exhibited moderate activities against Fusarium solani. Compound **10** showed a moderate activity against Candia albicans. Compound **5** was only moderately active against the Candida albicans.


Table 1. Studied compounds

## **2. Experimental**

26 Quantum Chemistry – Molecules for Innovations

5-fluoro-isatin -3-(*N*-benzylthiosemicarbazone) have recently been reported (Gunesdogdu-

During the current study, we prepared [Zn(HICHT)2], [Zn(HMIPT)2], [Zn(HIPT)2], [Zn(HICPT)2], [Zn(HIBT)2], [Ni(HMIPT)2], [Ni(HIPT)2], [Ni(HICPT)2], [Ni(HIBT)2], and [Ni(HICHT)2] derivatives, and characterized them with elemental analysis, and IR, UV, and

In view of the reports about antimicrobial and antifungal activities of the isatin derivatives, we synthesized and screened compounds **1-16** (Table 1) for their antimicrobial effects in vitro against Bacillus subtilis, Escherichia coli, Stahpylococcus aureus, Shigella flexnari, Pseudomonas aeruginosa, and Salmonella typhi bacterial strains and Aspergillus flavus, Candida albicans, Microsporum canis, Fusarium solani, and Candida glabrata fungal strains. Compounds **1**, **14**, and **16** were found to be moderately active, compounds **2**, and **4** possess a good activity, while compound **13** exhibited a significant activity against Microsporum canis. Compounds **13**, **12**, and **4** exhibited moderate activities against Fusarium solani. Compound **10** showed a moderate activity against Candia albicans.

1 5-Methoxyisatin-3-(N-cyclohexyl) thiosemicarbazone (H2MICT) 2 5-Methoxyisatin-3-(N-benzyl)thiosemicarbazone (H2MIBT) 3 5-Methoxyisatin-3-(N-phenyl)thiosemicarbazone (H2MIPT)

4 5-Methoxyisatin-3-(N-chlorophenyl)thiosemicarbazone (H2MICPT)

Compound **5** was only moderately active against the Candida albicans.

5 Isatin-3-(N-cyclohexyl)thiosemicarbazone(H2ICHT)

18 Isatin-3-(N-benzyl)thiosemicarbazone (H2IBT) 19 Isatin-3-(N-phenyl)thiosemicarbazone (H2IPT)

20 Isatin-3-(N-chlorophenyl)thiosemicarbazone (H2ICPT)

List of the Compounds

Sagdinc et al., 2009).

Compound

6 [Zn(HICHT)2] 7 [Zn((HMICT)2] 8 [Zn(HMIPT)2] 9 [Zn(HIPT)2] 10 [Zn(HICPT)2] 11 [Zn(HIBT)2] 12 [Ni((HMICHT)2] 13 [Ni(HMIPT)2] 14 [Ni(HIPT)2] 15 [Ni(HICPT)2] 16 [Ni(HIBT)2] 17 [Ni(HICHT)2]

Table 1. Studied compounds

No

1H-NMR spectroscopic techniques.

Elemental analyses were performed by using a LECO CHN Elemental Analyzer. IR Spectra were recorded by Shimadzu FT-IR 8201 spectrometer with the KBr technique in the region of 4000-300 cm-1, which was calibrated by polystyrene. There was no decomposition of the samples due to the effect of potassium bromide. The 1H-NMR spectra were recorded in DMSO-*d6* on a BRUKER DPX-400 (400 MHz) spectrometer.

The ligands under study were obtained by refluxing an ethanolic solution of 4-cyclohexyl-3 thiosemicarbazide, 4-benzyl-3-thiosemicarbazide, 4-phenyl-3-thiosemicarbazide, and 4-(4 chlorophenyl)-3-thiosemicarbazide with isatin (1H-indole-2,3-dione) or 5-methoxyisatin (all were purchased from Aldrich Chemical Company USA and used without purification), as described in the literature (Karali et al., 2007; Kandemirli et al., 2009a, 2009b**).**

## **2.1 General procedure for synthesis of Ni and Zn complexes**

1 mmol of appropriate ligand was dissolved in 20 mL of ethanol at 50-55 ºC and then slowly added to ethanol solution (10 mL) of 0.5 mmol zinc acetate dihydrate or nickel acetate tetrahydrate. The mixture was refluxed for 2 h for nickel complex, and 6 h for zinc complex at approximately 75 oC. The zinc complex precipated at the end of the reflux, while the nickel complex precipated only after two days of stirring. The solid was filtered, washed with ethanol, and diethyl ether, and dried under vacuum.

## **2.1.1 [Zn(HICHT)2] (6)**

Yield: (80%). (M.p.: 288-290 ºC)

1H-NMR (DMSO-*d6*, ppm): 1-2 (cyclohexyl C-H), 4.11 (m, cyclohexyl C-H), 6.90-8.3 (aromatic C-H), 8.95 (d, *J*= 7.8 Hz), NH 10.80 (s, indole-NH)

IR (cm-1): 1688 (C=O), 1595 (C=N), 819 (C=S)

Calculated: % C: 53.92, % H: 5.128, % N: 16.77, % S: 9.60, found: % C: 53.49, % H: 5.644, % N: 16.06, % S: 9.58.

## **2.1.2 [Zn(HMIPT)2] (8)**

Yield: (64%). (M.p.: 320 ºC)

1H-NMR (DMSO-*d6*, ppm): 3.35 (s, CH3-methoxy), 6.91-7.72 (aromatic C-H), 10.76 (s, NH), 11.04 (s, indole-NH)

IR (cm-1): 1697 (C=O), 1589 (C=N), 817 (C=S)

Calculated: % C: 53.67, % H: 3.66, % N: 15.64, % S: 8.95, found: % C: 53.64, % H: 3.65, % N: 15.67, % S: 9.08.

## **2.1.3 [Zn(HIPT)2] (9)**

Yield: (90%). (M.p.: 310 ºC)

1H-NMR (DMSO- *d6*, ppm): 7.01-8.11 (aromatic C-H), 10.68 (s, NH), 11.01 (s, indole-NH)

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 29

Calculated: % C: 56.73, % H: 3.86, % N: 16.54, % S: 9.46, found: % C: 56.35, % H: 3.84, % N:

Calculated: % C: 53.47, % H: 5.18, % N: 16.54, % S: 9.69, found: % C: 52.99, % H: 5.17, % N:

The antibacterial activities were determined by using the agar well diffusion method (Rahman et al., 2001). The wells were dugged in the media with a sterile borer and an eighthour-old bacterial inoculum containing 0>ca. 104-106 colony forming units (CFU)/mL were spread on the surface of the nutrient agar. The recommended concentration of the test sample (2 mg/mL in DMSO) was introduced into the respective wells. Other wells containing DMSO and the reference antibacterial drug imipenum served as negative and positive controls, respectively. The plates were incubated immediately at 37 oC for 20 h. The activity was determined by measuring the diameter of the inhibition zone (in mm), showing complete inhibition. Growth inhibition was calculated with reference to the positive control.

To test for antifungal activity, the agar dilution method, a modification of the agar dilution method of Washington and Sutter (980), was employed (Ajaiyeoba et al., 1988). Test tubes having sterile SDA were inoculated with test samples (200 mg/mL), and kept in a slanting position at room temperature. Test fungal culture was inoculated on the slant and growth inhibitions were observed after an incubation period of 7 days at 27 oC. Control agar tubes were made in paralellel and treated smilarly, except for the presence of test sample. Growth

All the quantum chemical calculations on the compounds **18***,* **5**, **19***,* and **20** were performed with full geometrical optimizations by using standard Gaussian 03 and 09 software package (Frisch et al., 2004). Geometrical optimization were carried out with two different methods, *ab initio* methods at the Hartree-Fock (HF) level, and density functional theory (DFT) by using the B3LYP change-correlation corrected functional (Becke, 1993; Lee et al., 1988) with 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p), LANL2DZ 6-31G(d,p) basis sets, and BP86/CEP-31G\* hybrid functional with 30% HF exchange and Stevens-Basch-Krauss pseudo potentials with polarized split valence basis sets (CEP-Compact Effective Potentials -31G\*) (Hill et al.,

inhibition was calculated with reference to positive control.

**2.4 Theoretical and computational details** 

**2.1.9 [Ni(HIBT)2] (16)** 

**2.1.10 [Ni(HICHT)2] (17)**  Yield: (90%). (M.p.: 265 ºC)

**2.2 Antibacterial activity** 

**2.3 Antifungal assay** 

1992; Stevens et al., 1984).

16.40, % S: 9.60.

16.14, % S: 9.37.

Yield (84%) (M.p.: 265-267 ºC)

IR (cm-1): 1659 (C=O), 1595 (C=N), 818 (C=S)

IR (cm-1): 1664 (C=O), 1595 (C=N), 823 (C=S)

IR (cm-1): 1703 (C=O), 1595 (C=N), 802 (C=S)

Calculated: % C: 54.92, % H: 3.38, % N: 17.08, % S: 9.77, found: % C: 54.52, % H:3.31, % N: 16.91, % S: 10.10.

### **2.1.4 [Zn(HICPT)2] (10)**

Yield: (82%) (M.p.: 321 ºC)

1H-NMR (DMSO-*d6*, ppm): 7.03-8.08 (aromatic C-H), 10.73 (s, NH), 11.06 (s, indole-NH)

IR (cm-1): 1695 (C=O), 1600 (C=N), 816 (C=S)

Calculated: % C: 48.69, % H: 2.78, % N: 15.45, % S: 8.84, found: % C: 48.43, % H: 3.03, % N: 14.96, % S: 8.81.

#### **2.1.5 [Zn(HIBT)2] (11)**

Yield: (79%) (M.p.: 318 ºC)

1H-NMR (DMSO-*d6*, ppm): 4.80 (d, benzyl-CH2), 6.95-7.40 (aromatic C-H), 9.45 (t, *J*=7.52 Hz), NH), 10.81 (s, indole-NH).

IR (cm-1): 1690 (C=O), 1599 (C=N), 814 (C=S)

Calculated: % C: 56.18, % H: 3.83, % N: 16.38, % S: 9.37, found: % C: 55.72, % H: 3.79, % N: 16.24, % S: 9.58.

#### **2.1.6 [Ni(HMIPT)2] (13)**

Yield: (90%) (M.p.: 300 ºC)

IR (cm-1): 1670 (C=O), 1589 (C=N), 818 (C=S),

Calculated: % C: 54.17, % H: 3.69, % N: 15.79, % S: 9.04, found: % C: 54.00, % H: 3.73, % N: 15.71, % S: 9.07.

#### **2.1.7 [Ni(HIPT)2] (14)**

Yield: (81%) (M.p.: 296 ºC)

IR (cm-1): 1660 (C=O), 1595 (C=N), 802 (C=S),

Calculated: % C: 52.48, % H: 3.41, % N: 16.25, % S: 9.87, found: % C: 52.79, % H: 3.60, % N: 16.24, % S: 9.33.

#### **2.1.8 [Ni(HICPT)2] (15)**

Yield: (70%) (M.p.: 265-267 ºC)

IR (cm-1): 1672 (C=O), 1595 (C=N), 817 (C=S)

Calculated: % C: 51.16, % H: 2.80, % N: 15.59, % S: 8.92, found: % C: 51.37, % H: 3.08, % N: 15.71, % S: 8.63.

## **2.1.9 [Ni(HIBT)2] (16)**

28 Quantum Chemistry – Molecules for Innovations

Calculated: % C: 54.92, % H: 3.38, % N: 17.08, % S: 9.77, found: % C: 54.52, % H:3.31, % N:

1H-NMR (DMSO-*d6*, ppm): 7.03-8.08 (aromatic C-H), 10.73 (s, NH), 11.06 (s, indole-NH)

Calculated: % C: 48.69, % H: 2.78, % N: 15.45, % S: 8.84, found: % C: 48.43, % H: 3.03, % N:

1H-NMR (DMSO-*d6*, ppm): 4.80 (d, benzyl-CH2), 6.95-7.40 (aromatic C-H), 9.45 (t, *J*=7.52

Calculated: % C: 56.18, % H: 3.83, % N: 16.38, % S: 9.37, found: % C: 55.72, % H: 3.79, % N:

Calculated: % C: 54.17, % H: 3.69, % N: 15.79, % S: 9.04, found: % C: 54.00, % H: 3.73, % N:

Calculated: % C: 52.48, % H: 3.41, % N: 16.25, % S: 9.87, found: % C: 52.79, % H: 3.60, % N:

Calculated: % C: 51.16, % H: 2.80, % N: 15.59, % S: 8.92, found: % C: 51.37, % H: 3.08, % N:

IR (cm-1): 1703 (C=O), 1595 (C=N), 802 (C=S)

IR (cm-1): 1695 (C=O), 1600 (C=N), 816 (C=S)

IR (cm-1): 1690 (C=O), 1599 (C=N), 814 (C=S)

IR (cm-1): 1670 (C=O), 1589 (C=N), 818 (C=S),

IR (cm-1): 1660 (C=O), 1595 (C=N), 802 (C=S),

IR (cm-1): 1672 (C=O), 1595 (C=N), 817 (C=S)

16.91, % S: 10.10.

14.96, % S: 8.81.

16.24, % S: 9.58.

15.71, % S: 9.07.

16.24, % S: 9.33.

15.71, % S: 8.63.

**2.1.7 [Ni(HIPT)2] (14)** 

Yield: (81%) (M.p.: 296 ºC)

**2.1.8 [Ni(HICPT)2] (15)** 

Yield: (70%) (M.p.: 265-267 ºC)

**2.1.6 [Ni(HMIPT)2] (13)**  Yield: (90%) (M.p.: 300 ºC)

**2.1.5 [Zn(HIBT)2] (11)**  Yield: (79%) (M.p.: 318 ºC)

Hz), NH), 10.81 (s, indole-NH).

**2.1.4 [Zn(HICPT)2] (10)**  Yield: (82%) (M.p.: 321 ºC) Yield (84%) (M.p.: 265-267 ºC)

IR (cm-1): 1659 (C=O), 1595 (C=N), 818 (C=S)

Calculated: % C: 56.73, % H: 3.86, % N: 16.54, % S: 9.46, found: % C: 56.35, % H: 3.84, % N: 16.40, % S: 9.60.

### **2.1.10 [Ni(HICHT)2] (17)**

Yield: (90%). (M.p.: 265 ºC)

IR (cm-1): 1664 (C=O), 1595 (C=N), 823 (C=S)

Calculated: % C: 53.47, % H: 5.18, % N: 16.54, % S: 9.69, found: % C: 52.99, % H: 5.17, % N: 16.14, % S: 9.37.

### **2.2 Antibacterial activity**

The antibacterial activities were determined by using the agar well diffusion method (Rahman et al., 2001). The wells were dugged in the media with a sterile borer and an eighthour-old bacterial inoculum containing 0>ca. 104-106 colony forming units (CFU)/mL were spread on the surface of the nutrient agar. The recommended concentration of the test sample (2 mg/mL in DMSO) was introduced into the respective wells. Other wells containing DMSO and the reference antibacterial drug imipenum served as negative and positive controls, respectively. The plates were incubated immediately at 37 oC for 20 h. The activity was determined by measuring the diameter of the inhibition zone (in mm), showing complete inhibition. Growth inhibition was calculated with reference to the positive control.

#### **2.3 Antifungal assay**

To test for antifungal activity, the agar dilution method, a modification of the agar dilution method of Washington and Sutter (980), was employed (Ajaiyeoba et al., 1988). Test tubes having sterile SDA were inoculated with test samples (200 mg/mL), and kept in a slanting position at room temperature. Test fungal culture was inoculated on the slant and growth inhibitions were observed after an incubation period of 7 days at 27 oC. Control agar tubes were made in paralellel and treated smilarly, except for the presence of test sample. Growth inhibition was calculated with reference to positive control.

#### **2.4 Theoretical and computational details**

All the quantum chemical calculations on the compounds **18***,* **5**, **19***,* and **20** were performed with full geometrical optimizations by using standard Gaussian 03 and 09 software package (Frisch et al., 2004). Geometrical optimization were carried out with two different methods, *ab initio* methods at the Hartree-Fock (HF) level, and density functional theory (DFT) by using the B3LYP change-correlation corrected functional (Becke, 1993; Lee et al., 1988) with 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p), LANL2DZ 6-31G(d,p) basis sets, and BP86/CEP-31G\* hybrid functional with 30% HF exchange and Stevens-Basch-Krauss pseudo potentials with polarized split valence basis sets (CEP-Compact Effective Potentials -31G\*) (Hill et al., 1992; Stevens et al., 1984).

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 31

Compound **14** Compound **9**

Values of the optimized geometrical parameters for all compounds are presented in Tables 2 and 3. The bond lengths, bond angles, and dihedral angles for compounds **18***,* **5**, **19***,* and **20** are almost the same as in isatin group. Mulliken charges of most atoms, except N and S, belong to thiosemicarbazone group are the same value. Therefore comparision among ligands, and deprotonated forms of ligand and complexes were made for compound **19**. In the deprotonated forms of **19**, as in N11-N12, C6-C7, and C13-C14, the bond lengths decrease, while C7-C9, C5-N8, and C4-C6 bond lengths increase. In Zn (II) complexes, C4-C6, C6-C7 bond lengths are similar to those of ligands. N11-N12 bond length in the deprotonated form of the ligands decreases, whereas in the complexes this bond length increases due to a transfer of charge from N atoms to metal. In the complex form, C-S bond length increases from 1.667 Å to 1.759 Å in Ni (II) complex, and 1.744 Å in

The calculated bond lengths of the Zn-S and Zn-N bonds for compound **9** were found to be 2.323 and 2.107 Å. The bond lengths of the Ni-N and Ni-S, Ni-O bonds for compound **14** 

Atoms **18 5 20 19 19a 9 14**  Bond distances (Å) C1-C2 1.396 1.396 1.396 1.396 1.408 1.396 1.395 C1-C3 1.399 1.399 1.399 1.399 1.396 1.398 1.399 C2-C4 1.396 1.396 1.395 1.395 1.382 1.393 1.396 C3-C5 1.385 1.385 1.385 1.385 1.385 1.386 1.385 C4-C6 1.390 1.390 1.390 1.390 1.406 1.393 1.394 C5-C6 1.411 1.411 1.411 1.411 1.424 1.413 1.417 C6-C7 1.456 1.456 1.455 1.456 1.418 1.455 1.450 C7-C9 1.502 1.502 1.503 1.502 1.548 1.525 1.502

Compounds

Fig. 1. Optimized structures of compounds **18**, **5**, **19**, **20**, **14**, **9**

Zn (II) complex.

Fukui functions, which are common descriptors of site reactivity and can be expressed by the following equations, were calculated by AOMix program (Gorelsky, 2009; Gorelsky & Lever, 2001).

> *fkk k N N* <sup>1</sup> (for nucleophilic attack) *f NN kk k* 1 (for electrophilic attack) 1 12 *<sup>o</sup> kk k fN N* (for radical attack)

Where, *k* represents the sites (atoms/molecular fragments) for nucleophilic, electrophilic and radical agents and *<sup>k</sup>* are their gross electron populations. An elevated value of *kf* implies a high reactivity of the site *k*.

### **3. Results and discussion**

The optimized structures of the compounds **18***,* **5**, **19***,* and **20** ligands, and the optimized structures of their corresponding Ni(II) and Zn(II) complexes are shown in Figure 1.

Fukui functions, which are common descriptors of site reactivity and can be expressed by the following equations, were calculated by AOMix program (Gorelsky, 2009; Gorelsky &

*fkk k N N* <sup>1</sup> (for nucleophilic attack)

*f NN kk k* 1 (for electrophilic attack)

*kk k fN N* (for radical attack)

Where, *k* represents the sites (atoms/molecular fragments) for nucleophilic, electrophilic

The optimized structures of the compounds **18***,* **5**, **19***,* and **20** ligands, and the optimized

Compound **18** Compound **5**

Compound **19** Compound **20** 

structures of their corresponding Ni(II) and Zn(II) complexes are shown in Figure 1.

*<sup>k</sup>* are their gross electron populations. An elevated value of *kf*

 

 1 12 *<sup>o</sup>*

 

Lever, 2001).

and radical agents and

implies a high reactivity of the site *k*.

**3. Results and discussion** 

Fig. 1. Optimized structures of compounds **18**, **5**, **19**, **20**, **14**, **9**

Values of the optimized geometrical parameters for all compounds are presented in Tables 2 and 3. The bond lengths, bond angles, and dihedral angles for compounds **18***,* **5**, **19***,* and **20** are almost the same as in isatin group. Mulliken charges of most atoms, except N and S, belong to thiosemicarbazone group are the same value. Therefore comparision among ligands, and deprotonated forms of ligand and complexes were made for compound **19**. In the deprotonated forms of **19**, as in N11-N12, C6-C7, and C13-C14, the bond lengths decrease, while C7-C9, C5-N8, and C4-C6 bond lengths increase. In Zn (II) complexes, C4-C6, C6-C7 bond lengths are similar to those of ligands. N11-N12 bond length in the deprotonated form of the ligands decreases, whereas in the complexes this bond length increases due to a transfer of charge from N atoms to metal. In the complex form, C-S bond length increases from 1.667 Å to 1.759 Å in Ni (II) complex, and 1.744 Å in Zn (II) complex.


The calculated bond lengths of the Zn-S and Zn-N bonds for compound **9** were found to be 2.323 and 2.107 Å. The bond lengths of the Ni-N and Ni-S, Ni-O bonds for compound **14** 

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 33

were 2.259, 1.903, and 2.830 Å, respectively. Experimental data of Ni-N and Ni-S, Ni-O bonds for the crystallographic analyses of complex of isatin--thiosemicarbazone were 2.023, 2.368, and 2.226 Å, respectively. The calculated dihedral angles C6-C7-N11-N12 and N12-C13-N14-C21 for compound **19** were 179.98o and -180.00o, respectively, very close to the crystal values of 5-methoxyisatin-3-(*N*-cyclohexyl)thiosemicarbazone) (Kandemirli et al.,

Atoms 18 5 20 19 19a 9 14 Dihedral angles (o) C3-C5-N8-C9 -180.00 179.96 - -179.99 -176.17 - - C5-C6-C7-N11 -180.00 -179.87 180.00 179.99 -178.71 176.47 -178.31 C5-N8-C9-O10 180.00 179.98 180.00 -179.98 176.75 179.62 175.86 N8-C9-C7-N11 180.00 179.85 -180.00 -179.98 -155.39 -176.13 179.37 C6-C7-N11-N12 -180.00 179.96 180.00 -179.98 28.48 177.24 1.70 C9-C7-N11-N12 0.00 0.08 0.00 0.01 -4.73 -5.54 -174.73 O10-C9-C7-N11 0.00 -0.07 0.00 -0.023 -147.12 2.76 1.58 C7-N11-N12-C13 -180.00 -179.78 -180.00 -179.99 123.93 176.10 160.68 N11-N12-C13-S15 180.00 179.55 -180.00 -180.00 -172.93 -3.78 -3.65 N12-C13-N14-C21 180.00 177.56 -179.98 -180.00 8.06 -0.22 -6.96 S15-C13-N14-C21 0.00 -2.69 0.02 0.00 -38.29 -179.42 176.54 C13-N14-C21-C24 179.99 - - - - - - N14-C21-C24-C25 89.51 -92.75 179.96 -91.29 142.56 5.42 156.43 N14-C21-C24-C26 -89.48 143.32 -0.04 91.24 142.56 -175.30 -79.66 Mulliken charges (ē) C5 0.239 0.239 0.240 0.239 0.261 0.253 0.245 C6 -0.134 -0.133 -0.136 -0.134 -0.110 -0.157 -0.140 C7 0.081 0.082 0.094 0.084 0.142 0.203 0.205 N8 -0.489 -0.489 -0.489 -0.489 -0.483 -0.490 -0.489 C9 0.421 0.420 0.423 0.421 0.436 0.614 0.376 O10 -0.360 -0.359 -0.357 -0.359 -0.231 -0.412 -0.322 N11 -0.225 -0.228 -0.240 -0.231 -0.207 -0.605 -0.476 N12 -0.274 -0.273 -0.270 -0.270 -0.082 -0.352 -0.266 C13 0.226 0.228 0.229 0.215 0.145 0.329 0.205 S15 -0.237 -0.244 -0.208 -0.201 0.163 -0.572 -0.317 N14 -0.405 -0.392 -0.463 -0.437 -0.381 -0.537 -0.379 Zn or Ni - - - - - 1.568 1.036

Table 3. Selected dihedral angles and Mulliken charges calculate with B3LYP/6-311G(d,p)

Compounds

2009a).

*<sup>a</sup>*Protonated form of 19

for compounds **18**, **5**, **20**, **19**, **9**, and **14** 


*<sup>a</sup>*Protonated form of 19

Table 2. Selected bond distances (Å) and bond angles charges calculate with B3LYP/6- 311G(d,p) for compounds **18**, **5**, **20**, **19**, **9**, and **14**

Table 2. Selected bond distances (Å) and bond angles charges calculate with B3LYP/6-

*<sup>a</sup>*Protonated form of 19

311G(d,p) for compounds **18**, **5**, **20**, **19**, **9**, and **14**

C5-N8 1.403 1.403 1.403 1.403 1.391 1.392 1.394 N8-C9 1.380 1.380 1.378 1.379 1.380 1.387 1.388 C7-N11 1.296 1.296 1.295 1.296 1.299 1.310 1.307 N11-N12 1.332 1.332 1.333 1.333 1.283 1.347 1.350 N12-C13 1.391 1.393 1.395 1.391 1.389 1.326 1.331 C13-S15 1.673 1.676 1.669 1.667 1.661 1.759 1.744 C13-N14 1.339 1.340 1.353 1.348 1.325 1.360 1.348 N14-C21 1.463 1.462 1.407 1.432 1.425 1.412 1.348 C21-C24 1.511 - - - - - - C24-C25 1.398 1.538 1.404 1.393 1.399 1.405 1.534 C24-C26 1.398 1.535 1.399 1.393 1.398 1.400 1.539 S15-Zn - - - - - 2.323 2.259 N11-Zn - - - - - 2.107 1.903 O10-Ni - - - - - - 2.830 Bond angles (o) C5-C6-C7 106.79 106.80 106.76 106.78 106.83 107.33 106.42 C6-C7-C9 107.02 107.00 107.01 107.01 107.29 106.47 107.54 C5-N8-C9 111.81 111.82 111.79 111.81 111.65 112.60 111.87 N8-C9-O10 126.91 126.87 105.29 105.29 104.17 124.43 126.18 C7-C9-O10 127.80 127.84 127.64 127.77 126.50 131.09 129.00 C7-N11-N12 119.25 119.25 119.33 119.29 126.94 116.83 117.32 C9-C7-N11 126.46 126.46 126.29 126.46 123.14 126.33 120.51 N11-N12-C13 120.79 121.01 121.47 120.93 116.34 117.34 112.11 N12-C13-S15 33.46 118.35 117.54 27.38 102.33 128.18 112.11 S15-C13-N14 125.98 127.13 130.01 126.98 135.52 113.71 118.44 C13-N14-C21 123.87 125.55 132.89 125.18 127.50 133.38 125.44 N14-C21-C24 110.10 109.87 115.97 119.79 117.49 115.70 109.61 C13-Zn/Ni-N11 - - - - - 91.80 90.93 S15- Zn/Ni -N11 - - - - - 130.33 95.84 N11- Zn/Ni -S15 - - - - - 123.82 84.44 O10-Ni-S15 - - - - - - 79.44 O10-Ni-O1 - - - - - - 74.20 O10-Ni-N11 - - - - - - 73.70

were 2.259, 1.903, and 2.830 Å, respectively. Experimental data of Ni-N and Ni-S, Ni-O bonds for the crystallographic analyses of complex of isatin--thiosemicarbazone were 2.023, 2.368, and 2.226 Å, respectively. The calculated dihedral angles C6-C7-N11-N12 and N12-C13-N14-C21 for compound **19** were 179.98o and -180.00o, respectively, very close to the crystal values of 5-methoxyisatin-3-(*N*-cyclohexyl)thiosemicarbazone) (Kandemirli et al., 2009a).


*<sup>a</sup>*Protonated form of 19

Table 3. Selected dihedral angles and Mulliken charges calculate with B3LYP/6-311G(d,p) for compounds **18**, **5**, **20**, **19**, **9**, and **14** 

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 35

A -1310.525279 -1274.797093 -1271.228351 -1730.859463 B -1310.516899 -1274.770217 -1271.201356 -1730.830654 C -1310.505963 -1274.758544 -1271.196548 -1730.826130 D -1310.492187 -1274.764865 -1271.207983 -1730.837828 E -1310.463311 -1274.737477 -1271.179113 -1730.808789 F -1310.466475 -1274.743568 -1271.175689 -1730.804186

Fukui functions values for compounds **18***,* **5**, **19***,* and **20** calculated with B3LYP/6-31G(d,p) were summarized in Table 5. The contribution of sulphur atom to the HOMO is 90.2% and 89.52% for compounds **18**, and **5***,* whereas, for compounds **19***,* and **20***,* the contribution of S decreases to 48.32%, and 41.90%, respectively. The other contributions for compound **19** comes from N14 atom (12.63%) belonging to thiosemicarbazone and phenyl groups (C24: 5.41%, C25: 5.65%, C25: 15%, C29: 1.93%, C25: 9.18%), and isatin group (C1: 1.49%, C5: 1.14%, C6: 1.06%, C7: 2.08%). For compound **5** contribution involves mostly N14 (13.45%), belonging to thiosemicarbazone group and phenyl ring (C24: 6.96%, C25: 5.75%, C25: 4.78%, C29: 2.76%, C25: 10.14%). Proportions of contribution change were according to the groups attached to N14 atom. Attaching phenyl group instead of cyclohexyl to N14 atom decreases

> For electrophilic attack C1 C5 C6 C7 O10 N12 C13 N14 S 15 C24 C25 C26 C29 C31

> > For nucleophilic attack

A - - - - - 1.06 4.26 - 90.20 - - - - - B - - - - - 1.35 4.09 - 89.52 1.12 - - - - C 1.49 1.14 1.06 2.08 1.10 2.05 - 12.63 48.32 5.41 5.65 4.15 1.93 9.18 D - - - 1.20 - - - 13.45 41.90 6.96 5.75 4.78 2.76 10.14

 C 1 C 4 C5 C6 C7 N8 C9 O10 N11 N12 C13 N14 S15 - A 6.69 5.03 3.98 3.61 12.92 1.46 10.45 8.96 26.63 5.35 4.45 2.16 6.98 - B 6.71 5.05 3.98 3.64 12.90 1.44 10.40 8.94 26.68 5.44 4.42 2.14 6.89 - C 6.52 5.01 3.94 3.26 13.23 1.39 9.95 8.70 25.21 4.57 5.39 1.86 8.12 - D 6.51 5.05 3.97 3.15 13.51 1.39 9.90 8.70 24.87 4.23 5.66 1.79 8.28 -

Table 5. Fukui functions for calculated with B3LYP/6-31G(d,p) for compounds **18***,* **5**, **19***,* and

The other molecular parameters, obtained through the theoretical calculations by using the level of B3LYP and RHF theory by using 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p) basis sets, are the EHOMO (highest occupied molecular orbital), and the ELUMO (lowest unoccupied molecular orbital). The highest occupied and the lowest unoccupied molecular orbital

Table 4. Electronic and zero point energy calculated with B3LYP/6-311G(d,p) for

the contribution of S atom to the HOMO orbital to approximately half.

Compounds **18 5 19 20** 

Tautomeric forms

compounds **18***,* **5**, **19***,* and **20** ligands

**3.2 Fukui functions** 

Tauto. Forms\*

\* Tautomeric forms

**20** ligands

Fig. 2. Possible tautomeric forms for compound **18** 

Calculated theoretical angle for **16** (C13-Ni-N11, S15-Ni -N11, N11-Ni -S15, O10-Ni-S15, O10-Ni-O1, O10-Ni-N11 were 90.93o, 95.84o, 84.44o, 79.44o, and 74.20o, respectively), which indicated that the complex is in a distorted octahedral coordination. Two terdentate monodeprotonated thiosemicarbazone groups, each of which is attached to the metal with the sulfur, the nitrogen atom from the hydrazine chain, and the carbonylic oxygen of the isatin moiety. The calculated dihedral angles of C3-C5-N8-C9, C6-C7-N11-N12o, N11-N12-C13-S15o were -179.99o, -179.98o, and -180.00o which showed that ligands are planar.

As presented in Table 3, Mulliken charges of C5, C6, N8, C9, and N12 were similar to each other in the neutral form. Most of the changes are on the N14 atom because of the changes in substituent attached to the N14 atom. The Mulliken charge of N14 atom was -0.405 ē for H2IBT*,* -0.392 ē for H2ICHT, -0.463 ē for H2IPT*,* and -0.437 ē for H2ICPT. Mulliken charges of atoms, both in the indole ring and thiosemicarbazone group, undergo a significant change, depending whether ligand is in the deprotonated form or in complexation process.

#### **3.1 The possible tautomeric forms of ligands**

The optimized structure for **18** ligand, calculated with B3LYP/6-311G(d,p), is shown in Figure 2. Electronic and zero point energies for compounds **18***,* **5**, **19***,* and **20** were given in Table 4. The most stable tautomeric form is A for studied ligands. In the form A, calculated electronic and zero point energy for compounds **18***,* **5**, **19***,* and **20** were -1310.525279 au, - 1274.797093 au, -1271.228351 au, and 1730.859463 au, respectively. Therefore, all discussions are based on A form.


Table 4. Electronic and zero point energy calculated with B3LYP/6-311G(d,p) for compounds **18***,* **5**, **19***,* and **20** ligands

#### **3.2 Fukui functions**

34 Quantum Chemistry – Molecules for Innovations

Calculated theoretical angle for **16** (C13-Ni-N11, S15-Ni -N11, N11-Ni -S15, O10-Ni-S15, O10-Ni-O1, O10-Ni-N11 were 90.93o, 95.84o, 84.44o, 79.44o, and 74.20o, respectively), which indicated that the complex is in a distorted octahedral coordination. Two terdentate monodeprotonated thiosemicarbazone groups, each of which is attached to the metal with the sulfur, the nitrogen atom from the hydrazine chain, and the carbonylic oxygen of the isatin moiety. The calculated dihedral angles of C3-C5-N8-C9, C6-C7-N11-N12o, N11-N12-C13-S15o were -179.99o, -179.98o, and -180.00o which

As presented in Table 3, Mulliken charges of C5, C6, N8, C9, and N12 were similar to each other in the neutral form. Most of the changes are on the N14 atom because of the changes in substituent attached to the N14 atom. The Mulliken charge of N14 atom was -0.405 ē for H2IBT*,* -0.392 ē for H2ICHT, -0.463 ē for H2IPT*,* and -0.437 ē for H2ICPT. Mulliken charges of atoms, both in the indole ring and thiosemicarbazone group, undergo a significant change, depending whether ligand is in the deprotonated form or in complexation

The optimized structure for **18** ligand, calculated with B3LYP/6-311G(d,p), is shown in Figure 2. Electronic and zero point energies for compounds **18***,* **5**, **19***,* and **20** were given in Table 4. The most stable tautomeric form is A for studied ligands. In the form A, calculated electronic and zero point energy for compounds **18***,* **5**, **19***,* and **20** were -1310.525279 au, - 1274.797093 au, -1271.228351 au, and 1730.859463 au, respectively. Therefore, all discussions

Fig. 2. Possible tautomeric forms for compound **18** 

**3.1 The possible tautomeric forms of ligands** 

showed that ligands are planar.

process.

are based on A form.

Fukui functions values for compounds **18***,* **5**, **19***,* and **20** calculated with B3LYP/6-31G(d,p) were summarized in Table 5. The contribution of sulphur atom to the HOMO is 90.2% and 89.52% for compounds **18**, and **5***,* whereas, for compounds **19***,* and **20***,* the contribution of S decreases to 48.32%, and 41.90%, respectively. The other contributions for compound **19** comes from N14 atom (12.63%) belonging to thiosemicarbazone and phenyl groups (C24: 5.41%, C25: 5.65%, C25: 15%, C29: 1.93%, C25: 9.18%), and isatin group (C1: 1.49%, C5: 1.14%, C6: 1.06%, C7: 2.08%). For compound **5** contribution involves mostly N14 (13.45%), belonging to thiosemicarbazone group and phenyl ring (C24: 6.96%, C25: 5.75%, C25: 4.78%, C29: 2.76%, C25: 10.14%). Proportions of contribution change were according to the groups attached to N14 atom. Attaching phenyl group instead of cyclohexyl to N14 atom decreases the contribution of S atom to the HOMO orbital to approximately half.


\* Tautomeric forms

Table 5. Fukui functions for calculated with B3LYP/6-31G(d,p) for compounds **18***,* **5**, **19***,* and **20** ligands

The other molecular parameters, obtained through the theoretical calculations by using the level of B3LYP and RHF theory by using 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p) basis sets, are the EHOMO (highest occupied molecular orbital), and the ELUMO (lowest unoccupied molecular orbital). The highest occupied and the lowest unoccupied molecular orbital

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 37

Compound **20**-HOMO Compound **20**-LUMO Compound **20**-electron

Fig. 3. HOMO, LUMO and electron density calculated at the level of B3LYP/6-311++G(d,p)

Thiosemicarbazones can coordinate with metal ions as neutral ligands (HTSC) or as anionic species (TSC) upon deprotonation at the N(2') (Beraldo & Tosi, 1983, 1986; Borges et al.,

Metal acetates with the ligands (H2L) lead to isolation of complexes of formula M(HL)2 (Rodriguez-Argiielles et al., 1999). As seen from the C, H, N analyses, the synthesized complexes are with the formula M(HL)2 (if the ligand is written as H2IPT*,* then complex has the formula of M(HIPT)2) *and* form 2:1 ligand-to-metal complexes which two of the ligands

Infrared absorptions in the range of 4000-400 cm-1 have been calculated for **19** with the method, B3LYP/6-31G(d,p), B3LYP/6-311G(d,p) and B3LYP/6-311++G(d,p) and for their Zn(II) and Ni (II) complexes with the method B3LYP/6-31G(d,p), B3LYP/6-311G(d,p), and B3LYP/LanL2DZ. Beside this, infrared frequencies for compounds **18**, **5**, and **20**, and their zinc (II) and nickel (II) complexes have been calculated. Calculated bands and their correspondence experimental values are presented in Tables 7 and 8. Loosing of N12 H

Energy 6-31G(d,p) 6-311G(d,p) 6-311G++(d,p) LANL2DZ **(a)** RHF B3LYP RHF B3LYP RHF B3LYP RHF B3LYP 6' 0.18055 0.01472 0.14439 0.00491 0.05089 -0.03326 0.16053 0.00090 5' 0.15887 0.00827 0.13996 -0.00377 0.04569 -0.03286 0.13557 -0.00545 4' 0.13325 -0.01245 0.12068 -0.02526 0.04149 -0.03142 0.11213 -0.02372 3' 0.13102 -0.01563 0.12043 -0.02712 0.03267 -0.01705 0.11212 -0.02547 2' 0.12559 -0.01632 0.11615 -0.02911 0.03241 -0.00870 0.10372 -0.03112 1' 0.04691 -0.08870 0.04111 -0.09642 0.02804 -0.01309 0.02603 -0.10317 1 -0.29966 -0.20958 -0.30438 -0.21286 -0.30635 -0.22160 -0.30530 -0.21316 2 -0.31169 -0.21266 -0.31672 -0.21770 -0.31882 -0.22471 -0.31549 -0.21892 3 -0.32555 -0.21266 -0.32999 -0.24209 -0.33211 -0.24364 -0.33497 -0.24024 4 -0.34287 -0.24654 -0.34749 -0.25866 -0.34886 -0.25832 -0.35162 -0.25603 5 -0.34330 -0.25940 -0.34807 -0.26857 -0.34983 -0.27125 -0.35190 -0.26582 6 -0.34878 -0.26066 -0.35334 -0.26974 -0.35503 -0.27277 -0.35772 -0.26721

band due to deprotonation is one of the main changes (Bresolin et al., 1997).

theory for compounds **18**, **5**, **19**, and **20** 

**3.3 IR spectra** 

were anionic.

MO

1997; Rejane et al., 1999).

density

energies (EHOMO and ELUMO), and the five molecular orbital energies for the nearest frontier orbitals of compounds **18***,* **5**, **19***,* and **20** were presented in Table 6*.* HOMO and LUMO electron densities for compounds **18***,* **5**, **19***,* and **20** which are calculated with B3LYP/6- 311++G(d,p) and shown in Figure 3. EHOMO values, obtained with B3LYP method, are higher than those of RHF method. Calculated EHOMO at the level of RHF/6-311G(d,p) and B3LYP/6-311G(d,p) theory are -0.30438 au and -0.21286 au for **18**; 0.30266 au and -0.21701 au for **5**; -0.30386 au and -0.21656 au for **19**; and -0.30899 au and -0.22050 au for compound **20**. HOMO of compounds **5**, **18***,* and **19** consist of mainly S atom belonging to the thiosemicarbazone group, and HOMO of compound **20** includes mainly S and chlorophenyl group. LUMO orbitals are distributed mainly over isatin and thiosemicarbazone groups for compounds **18***,* **5**, **19***,* and **20.** 

Electron densities for compounds **18***,* **5**, **19***,* and **20** are also shown in Figure 3. As shown in Figure 3, electron rich regions shown as red are found in the vicinity of the double bonded O and S atoms attached to C which belongs to isatin moiety and thiosemicarbazone moiety, respectively. Electron poor regions shown as blue, are mainly consists of N-H atoms belonging to isatin group.

Fig. 3. HOMO, LUMO and electron density calculated at the level of B3LYP/6-311++G(d,p) theory for compounds **18**, **5**, **19**, and **20** 

#### **3.3 IR spectra**

36 Quantum Chemistry – Molecules for Innovations

energies (EHOMO and ELUMO), and the five molecular orbital energies for the nearest frontier orbitals of compounds **18***,* **5**, **19***,* and **20** were presented in Table 6*.* HOMO and LUMO electron densities for compounds **18***,* **5**, **19***,* and **20** which are calculated with B3LYP/6- 311++G(d,p) and shown in Figure 3. EHOMO values, obtained with B3LYP method, are higher than those of RHF method. Calculated EHOMO at the level of RHF/6-311G(d,p) and B3LYP/6-311G(d,p) theory are -0.30438 au and -0.21286 au for **18**; 0.30266 au and -0.21701 au for **5**; -0.30386 au and -0.21656 au for **19**; and -0.30899 au and -0.22050 au for compound **20**. HOMO of compounds **5**, **18***,* and **19** consist of mainly S atom belonging to the thiosemicarbazone group, and HOMO of compound **20** includes mainly S and chlorophenyl group. LUMO orbitals are distributed mainly over isatin and thiosemicarbazone groups for

Electron densities for compounds **18***,* **5**, **19***,* and **20** are also shown in Figure 3. As shown in Figure 3, electron rich regions shown as red are found in the vicinity of the double bonded O and S atoms attached to C which belongs to isatin moiety and thiosemicarbazone moiety, respectively. Electron poor regions shown as blue, are mainly consists of N-H atoms

Compound **18**-HOMO Compound **18**-LUMO Compound **18**-electron

Compound **5**-HOMO Compound **5**-LUMO Compound **5**-electron

Compound **19**-HOMO Compound **19**-LUMO Compound **19**-electron

density

density

density

compounds **18***,* **5**, **19***,* and **20.** 

belonging to isatin group.

Thiosemicarbazones can coordinate with metal ions as neutral ligands (HTSC) or as anionic species (TSC) upon deprotonation at the N(2') (Beraldo & Tosi, 1983, 1986; Borges et al., 1997; Rejane et al., 1999).

Metal acetates with the ligands (H2L) lead to isolation of complexes of formula M(HL)2 (Rodriguez-Argiielles et al., 1999). As seen from the C, H, N analyses, the synthesized complexes are with the formula M(HL)2 (if the ligand is written as H2IPT*,* then complex has the formula of M(HIPT)2) *and* form 2:1 ligand-to-metal complexes which two of the ligands were anionic.

Infrared absorptions in the range of 4000-400 cm-1 have been calculated for **19** with the method, B3LYP/6-31G(d,p), B3LYP/6-311G(d,p) and B3LYP/6-311++G(d,p) and for their Zn(II) and Ni (II) complexes with the method B3LYP/6-31G(d,p), B3LYP/6-311G(d,p), and B3LYP/LanL2DZ. Beside this, infrared frequencies for compounds **18**, **5**, and **20**, and their zinc (II) and nickel (II) complexes have been calculated. Calculated bands and their correspondence experimental values are presented in Tables 7 and 8. Loosing of N12 H band due to deprotonation is one of the main changes (Bresolin et al., 1997).


Quantum Chemical Calculations for some Isatin Thiosemicarbazones 39

The FT-IR spectra for **19** shows bands at 3298, 3244, 3177, 1703, and 1612 cm–1, assigned to stretching vibration modes νN(8)H, N(14)H, νC=O and νC=N, respectively. Stretching vibration modes of νN(8)H, νN(14)H, νC=O, and νC=N were found at 3372, 3179, 1703, and 1612 cm–1 for its zinc (II) complex and at 3381, 3271, 1661, and 1614 cm–1 for nickel (II) complex, respectively. The IR peak of N(12)-H of thiosemicarbazide regions at 3283, 3244, 3242, and 3242 cm-1 in the spectra of compounds **18***,* **5**, **19***,* and **20** ligands are not present in their zinc (II), and nickel (II) complexes, due to proton dissociation, which is the main change (Bresolin et al., 1997). Infrared spectra of the *ν*(C=N) for compounds **5**, **18***,* **19**, and **20** ligands were assigned as 1618, 1620, 1620, and 1622 cm−1, respectively. In their nickel (II) and zinc (II) complexes, the position of these bands shifted to 1595 cm−1. On complex

(cm-1) Intensity Assignment

(C27-H)ring C, (C29-H)ring C

(C27-H)ring C, (C29-H)ring C

combination

δ(N14H)

δ(N12H)

formation with nickel (II), and zinc (II), C=S band shifted towards the lower side.

 3198 16 3198 13 (CH)ring A combination 3148 3254 12 3198 4 3197 4 (C26-H)ring C combination

3071 3216 18 3189 17 3189 13 (CH)ring A combination 3059 3210 27 3186 27 3185 23 (CH)ring C combination 3207 18 3181 5 3181 5 (CH)ring A combination 3200 5 (CH)ring A combination

3194 15 3193 12 (C25-H)ring C, (C26-H)ring C,

3028 3196 22 3176 6 3175 5 (C25-H)ring C, (C26-H)ring C,

1594 1675 91 1661 98 1658 94 (CC)ring A combination, δ(N8H) 1539 1661 25 1644 14 1641 15 (CC)ring A combination, δ(N14C13) 1492 1652 124 (CC)ring C combination, δ(N14H) 1636 21 1632 15 (CC)ring A combination 1477 1649 16 (CC)ring A combination 1630 3 1627 3 (CC)ring C combination

1462 1637 175 1623 191 1618 216 (C7-N11), δ(N12H), (CC)ring C

1439 1598 750 1544 620 1539 542 δ(N14H), δ(CH)ring C combination 1412 1541 74 δ(CH) ring C combination, δ(N12H),

1525 190 1522 183 δ(CH) ring A combination, δ(N8H),

 3168 12 (CH)ring C combination 1694 1790 222 1775 257 1758 297 ( C=O), δ(N8H), δ(N12H)

(cm-1) Intensity Freq.

3298 3661 75 3642 71 3640 75 (N8H)indole 3244 3516 86 3540 96 3543 94 (N14H)tiyo 3177 3432 91 3437 85 3433 84 (N12H)tiyo

6-31G(d,p) 6-311G(d,p) 6-311++G(d,p)

Exp. Freq.

Compound **19**

1620

(cm-1) Intensity Freq.


Table 6. Calculated values for the highest occupied and the lowest unoccupied molecular orbital energies HOMO and LUMO, and the five molecular orbital energy the nearest frontier orbitals for (a) **18***,* (b) **5**, (c) **19***,* and (d) **20**

6' 0.22036 0.07889 0.15398 0.03320 0.05283 -0.00555 0.22904 0.07491 5' 0.21615 0.07539 0.14812 0.02913 0.04826 -0.00929 0.21900 0.07219 4' 0.18048 0.01426 0.14059 0.00407 0.04213 -0.01325 0.16181 0.00122 3' 0.15787 0.00751 0.13494 -0.00274 0.03393 -0.01759 0.13511 -0.00560 2' 0.12486 -0.01671 0.11558 -0.02654 0.03241 -0.03341 0.10324 -0.03120 1' 0.04648 -0.08890 0.04082 -0.09696 0.02768 -0.10207 0.02635 -0.10269 1 -0.29829 -0.20836 -0.30266 -0.21701 -0.30407 -0.21948 -0.30214 -0.21091 2 -0.31042 -0.21108 -0.31499 -0.21922 -0.31631 -0.22241 -0.31288 -0.21568 3 -0.32484 -0.22993 -0.32907 -0.23819 -0.33081 -0.24172 -0.33388 -0.23854 4 -0.34721 -0.24596 -0.35142 -0.25421 -0.35263 -0.25725 -0.35609 -0.25495 5 -0.39928 -0.26914 -0.40313 -0.27761 -0.40410 -0.28176 -0.40838 -0.27693 6 -0.43098 -0.28528 -0.43466 -0.29358 -0.43699 -0.29626 -0.43871 -0.29228

6' 0.18135 0.03242 0.14358 0.00235 0.05130 -0.01079 0.17626 0.01936 5' 0.15783 0.00696 0.13850 -0.00421 0.04653 -0.01753 0.13359 -0.00865 4' 0.14350 -0.00375 0.13029 -0.01837 0.04127 -0.02585 0.12023 -0.01588 3' 0.13463 -0.02009 0.12802 -0.02132 0.03540 -0.02825 0.10782 -0.03380 2' 0.12322 -0.02198 0.11434 -0.02779 0.02997 -0.03488 0.09968 -0.03534 1' 0.04323 -0.09503 0.03855 -0.09899 0.02732 -0.10450 0.01959 -0.10946 1 -0.29931 -0.21623 -0.30386 -0.21656 -0.30594 -0.21996 -0.30582 -0.22084 2 -0.30783 -0.21628 -0.31251 -0.22104 -0.31487 -0.22489 -0.32135 -0.22190 3 -0.32430 -0.22239 -0.33168 -0.24187 -0.33378 -0.24588 -0.32368 -0.23349 4 -0.33602 -0.24315 -0.34277 -0.25858 -0.34444 -0.26205 -0.34504 -0.25289 5 -0.34001 -0.25398 -0.34717 -0.26456 -0.34914 -0.26793 -0.34924 -0.26157 6 -0.35686 -0.27301 -0.35596 -0.26571 -0.35765 -0.26889 -0.37209 -0.28058

6' 0.17471 0.02265 0.13955 0.01052 0.05007 -0.02179 0.15295 0.00965 5' 0.15375 0.00354 0.13592 -0.00666 0.04981 0.00440 0.12967 -0.01248 4' 0.12806 -0.01734 0.11543 -0.02957 0.04023 0.00291 0.10620 -0.03124 3' 0.12168 -0.02339 0.11423 -0.03312 0.03302 -0.01424 0.10191 -0.03896 2' 0.11948 -0.03026 0.11139 -0.04013 0.02637 -0.00571 0.09757 -0.04281 1' 0.03893 -0.09939 0.03459 -0.10727 0.02552 -0.01692 0.01736 -0.11453 1 -0.30480 -0.22050 -0.30899 -0.22895 -0.31067 -0.23154 -0.31149 -0.22767 2 -0.31382 -0.22213 -0.31803 -0.23052 -0.31983 -0.23281 -0.32058 -0.22812 3 -0.32819 -0.22582 -0.33599 -0.23414 -0.33779 -0.23730 -0.34034 -0.23818 4 -0.33930 -0.24652 -0.34810 -0.25459 -0.34911 -0.25774 -0.35297 -0.25692 5 -0.35484 -0.26768 -0.35724 -0.27708 -0.35800 -0.27925 -0.36610 -0.28266 6 -0.36077 -0.27427 -0.36142 -0.28272 -0.36254 -0.28521 -0.37048 -0.27736 HOMOLUMO: 1 1'

Table 6. Calculated values for the highest occupied and the lowest unoccupied molecular orbital energies HOMO and LUMO, and the five molecular orbital energy the nearest

frontier orbitals for (a) **18***,* (b) **5**, (c) **19***,* and (d) **20**

**(b)** 

**(c)** 

**(d)**

The FT-IR spectra for **19** shows bands at 3298, 3244, 3177, 1703, and 1612 cm–1, assigned to stretching vibration modes νN(8)H, N(14)H, νC=O and νC=N, respectively. Stretching vibration modes of νN(8)H, νN(14)H, νC=O, and νC=N were found at 3372, 3179, 1703, and 1612 cm–1 for its zinc (II) complex and at 3381, 3271, 1661, and 1614 cm–1 for nickel (II) complex, respectively. The IR peak of N(12)-H of thiosemicarbazide regions at 3283, 3244, 3242, and 3242 cm-1 in the spectra of compounds **18***,* **5**, **19***,* and **20** ligands are not present in their zinc (II), and nickel (II) complexes, due to proton dissociation, which is the main change (Bresolin et al., 1997). Infrared spectra of the *ν*(C=N) for compounds **5**, **18***,* **19**, and **20** ligands were assigned as 1618, 1620, 1620, and 1622 cm−1, respectively. In their nickel (II) and zinc (II) complexes, the position of these bands shifted to 1595 cm−1. On complex formation with nickel (II), and zinc (II), C=S band shifted towards the lower side.


Quantum Chemical Calculations for some Isatin Thiosemicarbazones 41

3178 26 (C26-H)ring C, (C27-H)ring C, (C29-

3178 19 (C26-H)ring C, (C27-H)ring C, (C29-

H)ring C

H)ring C

3023 3208 77 3198 23 3234 35 (CH)ring A combination 3204 14 3203 4 (CH)ring A combination 3204 11 (CH)ring A combination 3195 29 3191 71 (CH)ring C combination 3195 19 3198 3 (CH)ring C combination 3190 4 3186 15 (CH)ring C combination 3186 10 (CH)ring C combination

3173 4 (CH)ring A combination

1703 1808 509 1794 559 1690 22 (C-O) 1808 10 1794 7 1690 436 (C-O)

1508 1603 51 1593 42 1582 24 (N11C7) 1602 12 1592 13 1582 66 (N11C7)

 3165 6 3150 6 3175 4 (C26-H)ring C, (C29-H)ring C 3165 13 3150 11 3175 18 (C26-H)ring C, (C29-H)ring C

1612 1674 184 1652 192 1671 243 δ(N8H), (CC)ring A combination 1674 21 1661 19 1671 48 δ(N8H), (CC)ring A combination 1656 10 1642 6 1649 6 δ(N14H), (CC)ring C combination 1648 4 1642 6 1649 5 δ(N14H), (CC)ring C combination 1595 1648 54 1636 73 1643 48 δ(N14H), (CC)ring C combination 1642 16 1631 18 1639 28 δ(N8H), (CC)ring A combination

 1582 5 1576 10 δ(N14H), (CC)ring C combination 1456 1578 635 1572 591 1573 423 δ(N14H), (CC)ring C combination 1537 181 1525 183 1525 10 δ(N14H), (CC)ring C combination 1526 12 1516 13 1524 273 δ(N8H), (CC)ring A combination

 1489 128 1479 90 1478 55 δ(N14H), (CC)ring C combination 1488 100 1478 70 1477 76 δ(N14H), (CC)ring C combination 1338 1464 1142 1446 1189 1451 837 (N11C7), (N12C13), (CH)ring C 1462 2109 1444 2160 1451 1948 (N11C7), (N12C13), (CH)ring C 1277 1428 89 1420 129 1431 74 δ(N8H), (CC)ring A combination 1371 41 1363 60 1386 40 δ(N14H), (CC)ring C combination

 1366 101 1358 119 1377 127 δ(N8H), (CC)ring A combination 1348 17 1373 5 δ(N14H), (CC)ring C combination 1361 164 1347 155 1373 95 δ(N14H), (CC)ring C combination

1144 1272 143 1265 138 1300 221 (indole ring), (NH)semicarbazone

 1510 5 1500 9 1501 15 (CC)ring A combination 1396 1510 160 1500 179 1501 218 (CC)ring A combination

1242 1368 81 1359 138 1378 101 (NH), (CH)

1094 1204 228 1192 222 1273 39 (CH)indole+(C-S)

1178 1324 32 1312 24 1333 45 (isatin)


δ(N12H)

combination,δ(N14H)

(indole ring)

1377 1531 168 δ(CH) ring A combination, δ(N8H),

1341 1522 54 1513 17 1510 17 isatin, δ(N12H)

1298 1487 64 1483 4 1480 4 δ(CH) ring C combination 1271 1429 148 1418 58 1415 56 δ(N8H), δ(CH) ring A

 1407 212 1385 128 1380 136 δ(N14H), (N12C13) 1248 1369 28 ω(ring A), δ(N14H) 1227 1365 39 ω(ring A, B, C) 1355 72 1353 73 ω(isatin)

1101 1127 14 1122 24 1121 28 (ring A) 1028 1059 7 1048 9 1047 11 (phenyl) 982 1048 3 1021 5 1020 4 (phenyl ring) 964 1000 1 1000 4 999 6 (indole ring)

1207 1354 23 1312 16 1311 17 δ(NH), δ(CH) ring A combination 1148 1198 895 1189 935 1187 836 (N-N)+δ(ring A)+(C-N) 1136 1183 153 1179 212 1177 336 (C-N)+δ(ring A)+(C-N)

941 961 38 955 25 953 23 (phenyl ring)+(N-H)

793 817 100 823 80 822 81 (phenyl ring)+(indole ring) 760 797 45 806 32 796 29 (N-H)thio+(C-C)indole ring+

679 763 21 738 54 733 44 (N-H)thio+(indole ring)

503 514 109 517 169 509 107 (N-H)indole+(N-H)thio

644 697 9 691 18 690 16 (indole ring)+(phenyl ring) 590 673 18 659 19 658 19 (phenyl ring )+(C-S)

903 940 1 932 15 932 15 (phenyl ring) 864 889 7 890 7 889 6 (indole ring)

700 771 64 761 33 757 45 (indole ring)

658 716 97 710 40 707 44 (phenyl ring)

480 490 24 458 17 456 19 (phenyl ring)

3372 3667 66 3649 68 3674 37 (N8H)indole 3667 70 3649 70 3674 105 (N8H)indole 3179 3615 99 3601 106 3596 98 (N14H)thio 3615 105 3601 107 3596 142 (N14H)thio 3150 3260 28 3242 26 3272 20 (C25-H)ring C 3242 105 3272 121 (C25-H)ring C 3063 3260 116 3266 14 (CH)ring A combination 3215 10 3198 7 3234 22 (CH)ring A combination 3214 27 (CH)ring A+(CH)ring C

561 592 8 624 13 620 13 (C-S)

Compound **9**

1522 110 1519 139 δ(CH) ring C combination, δ(N14H)

1316 1505 143 1494 143 1492 138 δ(CH) ring A combination, δ(N12H)


Quantum Chemical Calculations for some Isatin Thiosemicarbazones 43

1496 1572 265 1571 139 (CC)ring C combination , δ(N14H) 1569 645 1562 611 1568 539 (CC)ring C combination , δ(N14H) 1456 1539 61 1527 69 1527 172 (CH)ring C combination , δ(N14H) 1538 130 1527 133 1526 311 (CH)ring C combination , δ(N14H)

 1525 86 1514 81 1512 16 (isatin), (N-C-N) 1525 68 1514 90 1511 26 (isatin), (N-C-N) 1408 1501 259 1492 303 1490 8 (CC)ring A combination , δ(N8H) 1501 172 1492 333 1489 145 (CC)ring A combination , δ(N8H) 1498 220 1488 153 1480 65 (CC)ring A, (CC)ring C, (CH), (NH)

1496 360 1487 228 1480 128 (CC)ring A, (CC)ring C,

1348 1478 790 1465 841 1456 1179 (CC)ring C, (N-C-N) 1475 687 1463 691 1453 1020 (CC)ring C, (N-C-N) 1315 1422 80 1414 62 1428 147 (CC)ring A combination, δ(N8H) 1421 87 1414 74 1428 145 (CC)ring A combination, δ(N8H) 1369 29 1357 31 1385 10 (CC)ring C combination, δ(N14H) 1275 1369 54 1356 309 1372 276 (CC)ring A, (CC)ring C, (NH) 1364 223 1355 187 1371 141 (CC)ring A, (CC)ring C, (NH) 1364 193 (CC)ring A, (CC)ring C, (NH)

 1356 5 1365 27 (CH)ring C combination 1229 1356 238 1344 278 1365 169 (CH)ring C combination

1143 1272 143 1286 71 1304 96 (NN)+(CH)indole 1094 1244 10 1265 195 1265 177 ω(indole ring)+ω(N-H) 1045 1204 228 1237 45 1257 128 (Cphenyl-N)+(NH)semicarbazone

1009 1202 253 1194 693 1229 261 ω(phenyl ring) 937 1176 443 1148 343 1206 45 (NN)+(phenyl) 903 1129 79 1116 107 1189 680 (indole ring) 881 1055 3 1029 35 1148 215 (indole ring)

802 943 2 895 13 1026 55 (C-N+N-H) 777 858 9 851 46 951 17 (indole ring) 748 807 154 819 19 841 43 (C-S)+(Ni-N) 694 795 62 765 45 792 132 (phenyl ring)

421 575 25 572 25 562 25 (Ni-N) 327 319 8 362 21 269 5 (Ni-S)

(II) complexes with their tentative assignment

839 998 64 915 12 1059 28 (indole ring)+(C-N)

657 705 19 663 17 631 29 (N-H)+ω(phenyl ring)

Table 7. The experimental and calculated infrared frequencies at the level of B3LYP/6- 31G(d,p), B3LYP/6-311G(d,p) and B3LYP/6-311++G(d,p) theory for **19**, at the level of B3LYP/6-31G(d,p), B3LYP/6-311G(d,p), and B3LYP /LANL2DZ theory for its Zn(II) and Ni

1165 1309 91 1310 38 1338 43 (indole ring), (NH)semicarbazone

(N12C13), (N11C7)


1043 1176 443 1166 511 1222 124 (N-N)+(CH)indole 1007 1122 13 1125 111 1208 123 ω(indole ring) 966 998 64 1116 22 1187 347 ω(phenyl ring) 883 924 5 1000 25 1127 135 (indole ring)

833 858 9 995 54 1111 84 (indole ring)+(C-N)

611 630 30 706 25 800 121 (phenyl ring)+(N-H) 594 605 74 640 19 785 226 (N-H)+ω(phenyl ring)

(N11C7)

(N11C7)

 1642 13 1629 19 1638 74 (CC)ring A combination, δ(N8H), (N11C7) 1626 4 1612 9 1614 27 (CC)ring A combination, δ(N8H), (N11C7)

1518 1620 48 1566 184 1604 24 (CC)ring A combination, δ(N8H),

802 807 154 855 8 983 92 (phenyl ring) 783 795 62 824 28 974 10 (C-N+N-H) 750 771 46 799 216 894 9 (C-S)+(C-C)indole 690 705 19 768 54 846 18 (phenyl ring) 658 696 16 764 19 814 33 (indole ring)

550 537 19 637 34 725 60 (N-H)

3381 3671 103 3653 103 3680 97 (N8H)indole 3670 49 3653 48 3679 57 (N8H)indole 3271 3624 40 3610 40 3606 66 (N14H)thio 3624 92 3610 97 3606 81 (N14H)thio 3265 5 (C4H)ring A 3122 3210 19 3192 17 3230 24 (CH)ring C combination 3210 44 3192 40 3230 62 (CH)ring C combination 3209 10 3192 8 3230 20 (CH)ring A combination 3065 3209 57 3192 49 3229 66 (CH)ring A combination 3200 15 3182 16 3214 13 (CH)ring A combination 3200 13 3182 12 3214 18 (CH)ring A combination 3195 43 3178 40 3210 52 (CH)ring C combination 3173 14 3156 12 3210 4 (CH)ring C combination 3182 19 (CH)ring C combination 1661 1803 11 1801 24 1686 2 (isatin), (N11C7), (C-O) 1792 540 1792 620 1678 251 (isatin), (N11C7), (C-O) 1668 6 (isatin), (N11C7), (C-O) 1666 534 (isatin), (N11C7), (C-O) 1614 1670 216 1658 240 (CC)ring A combination, δ(N8H) 1660 32 1645 27 1653 25 (CC)ring C combination , δ(N14H) 1595 1659 65 1645 61 1652 87 (CC)ring C combination , δ(N14H) 1535 1648 16 1635 25 1643 39 (CC)ring C combination , δ(N14H) 1647 60 1634 80 1642 89 (CC)ring C combination , δ(N14H) 1643 22 1630 16 1640 11 (CC)ring A combination, δ(N8H),

Compound **14**


Table 7. The experimental and calculated infrared frequencies at the level of B3LYP/6- 31G(d,p), B3LYP/6-311G(d,p) and B3LYP/6-311++G(d,p) theory for **19**, at the level of B3LYP/6-31G(d,p), B3LYP/6-311G(d,p), and B3LYP /LANL2DZ theory for its Zn(II) and Ni (II) complexes with their tentative assignment

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 45

Compounds **5**, **18***,* **19**, and **20** were optimized by B3LYP method with 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p), and with density functional theory by using the BP86 hybrid functional with 30% HF exchange (B3P86-30%), and Stevens-Basch-Krauss pseudo potentials with polarized split valence basis sets (CEP-31G\*) (Stevens et al., 1984) and theoretical calculated wave numbers of electronic transitions for compounds **5**, **18***,* **19**, and **20** are reported in Tables 9 and

Experimental 252 268 278 288 296 372

Experimental 250 268 278 288 296 364 373

BP86 CEP-31G\* 227 240 257 312 382

Experimental 258 296 364 370

BP86 CEP-31G\* 216 253-238-226 305 352 382

Experimental 250 260 368 370

BP86 CEP-31G\* 236 256-254-245 338 390-382

The UV visible spectral values, excitation energies, and ossillator strengths were calculated at TDB3LYP levels by using 6-31G(d,p), 6-311Gs(d,p), 6-311++G(d,p) basis sets and TDBP86- CEP-31G\* level for compounds **5**, **18***,* **19**, and **20**. There was an agreement between the UV

The C=N transitions due to n– for isatin-3-thiosemicarbazones were assigned as 2070 cm-1 (483 nm) of (Akinchan et al., 2002). This band was found to be 372, 373, 370, 370 nm for compounds **5**, **18***,* **19**, and **20**, respectively. At the level of TDBP86-CEP-31G\*, this band for compounds **5**, **18***,* **19**, and **20** was found at 382 nm, which arises from 3-1', 2-1', 3-1', and 3-1' transitions. The bands due to –\* transitions of semicarbazone group for isatin-3 thiosemicarbazone were between the range of 400-286 nm (Akinchan et al., 2002). Band at

Table 9. Experimental and theoretical UV assignments for compounds **18, 5**, **19***,* and **20** calculated by using TDB3LYP with the 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p), BP86-CEP-

calculations at the level of TDBP86-CEP-31G\* for ligands, and experimental results.

6-31G(d,p) 219 233 249 264 326 399 6-311G(d,p) 209 222 236 266 326 401 6-311++G(d,p) 214 223 227 270 332 407 BP86 CEP-31G\* 210 225 238 255 309 378-349

> 6-31G(d,p) 210 236 252 267 327 406 6-311G(d,p) 212 228 -237 254 268 328 408 6-311++G(d,p) 216 242 259 272 334 415

> 6-31G(d,p) 207 249 254-256 355 400 6-311G(d,p) 210 224-236 264 321 405 6-311++G(d,p) 213 231-240-256 269 327 412

6-31G(d,p) 208 256-257-262 357 429-402 6-311G(d,p) 209 251-258-266 358 427-403 6-311++G(d,p) 209 256-261-269 363 436-409

10. Very weak features with oscillator strengths below 0.25 were omitted.

UV-Visible spectrum data (nm)

**3.4 Electronic spectrum** 

Comp. **18**

Comp. **5**

Comp. **19**

Comp. **20**

B3LYP

B3LYP

B3LYP

B3LYP

31G\* basis set


Table 8. Some important experimental and theoretical IR assignments

The frequency of the **ν(**C=O) vibration shifts to lower energy by (**ν** = 20-30 cm-1) upon coordination as the anion ligands (the frequency of the ν(C=O) vibration for compounds **5**, **19**, **18**, and **20** are 1684, 1693, 1693, 1693 cm-1, whereas for their nickel (II) complexes are 1664, 1660, 1659, and 1672 cm-1, which may be due to the transfer of a charge from the oxygen to the nickel (Mulliken charge on O10 atom for **19**, its zinc (II) and nickel (II) complexes are 0.359, 0.412, and -0.322, respectively). Thus, it was concluded that nickel (II) complexex co-ordinate through the oxygen of (C=O) in the indole ring, and nitrogen, and sulphur atoms, belonging to thiosemicarbazone and C=S groups. In the zinc (II) complexes, no shifting for ν(C=O) vibration occurred indicated that only thiosemicarbazone moiety of the compounds **5**, **18***,* **19**, and **20** ligands is coordinated in a bidentate way through N and S. In the far-infrared region for zinc (II) complexes, Zn-N, Zn-S vibrations were observed at 422, and 318 cm-1 for compound **6**; 430, and 329 for compound **10**; 420, and 333 cm-1 for compound **11**; 434, and 325 cm-1 for compound **9**; in nickel (II) complexes, Ni-N, Ni-O, and Ni-S were assigned at 420, 374, 316, for compound **17**; 434, 352, 20-1 for compound **15**; 424, 345, 329 cm-1 for compound **16**; 420, 346, 327 cm-1 for compound **14**.

### **3.4 Electronic spectrum**

44 Quantum Chemistry – Molecules for Innovations

Theoretical IR Experimental IR Compound *v*(*N*(8)*H*) *v*(*N*(14)*H*) *v*(*N*(12)*H*) *v*(*N*(8)*H*) *v*(*N*(14)*H*) *v*(*N*(12)*H*) 5 3919 3784 3843 3366 3283 3231 6 3924 - 3885 3379 - 3169 17 3925 - 3882 3296 - 3194 19 3919 3785 3843 3298 3244 3176 9 3922 - 3874 3372 - 3179 14 3924 - 3880 3381 - 3155 18 3919 3787 3858 3366 3242 3166 11 3924 - 3897 3169 - 3402 16 3925 - 3874 3167 - 3394 20 3918 3783 3841 3309 3242 3184 10 3920 - 3873 3348 - 3177 15 3922 - 3879 3383 - 3179

Compound *v*(*C* 0) *v*(*C N*) *v*(*C S*) *v*(*C* 0) *v*(*C N*) *v*(*C S*) 5 1887 1842 1181 1684 1618 864 6 1890 1817 1124 1688 1595 819 17 1834 1826 1138 1664 1595 823 19 1888 1845 1230 1693 1620 863 9 1898 1828 1124 1703 1595 802 14 1849 1838 1146 1660 1595 802 18 1888 1843 1209 1693 1620 862 11 1894 1828 1121 1690 1599 814 16 1659 1595 818 20 1890 1848 1229 1693 1622 864 10 1899 1830 1124 1695 1600 816 15 1852 1841 1146 1672 1595 817

The frequency of the **ν(**C=O) vibration shifts to lower energy by (**ν** = 20-30 cm-1) upon coordination as the anion ligands (the frequency of the ν(C=O) vibration for compounds **5**, **19**, **18**, and **20** are 1684, 1693, 1693, 1693 cm-1, whereas for their nickel (II) complexes are 1664, 1660, 1659, and 1672 cm-1, which may be due to the transfer of a charge from the oxygen to the nickel (Mulliken charge on O10 atom for **19**, its zinc (II) and nickel (II) complexes are 0.359, 0.412, and -0.322, respectively). Thus, it was concluded that nickel (II) complexex co-ordinate through the oxygen of (C=O) in the indole ring, and nitrogen, and sulphur atoms, belonging to thiosemicarbazone and C=S groups. In the zinc (II) complexes, no shifting for ν(C=O) vibration occurred indicated that only thiosemicarbazone moiety of the compounds **5**, **18***,* **19**, and **20** ligands is coordinated in a bidentate way through N and S. In the far-infrared region for zinc (II) complexes, Zn-N, Zn-S vibrations were observed at 422, and 318 cm-1 for compound **6**; 430, and 329 for compound **10**; 420, and 333 cm-1 for compound **11**; 434, and 325 cm-1 for compound **9**; in nickel (II) complexes, Ni-N, Ni-O, and Ni-S were assigned at 420, 374, 316, for compound **17**; 434, 352, 20-1 for compound **15**; 424,

Table 8. Some important experimental and theoretical IR assignments

345, 329 cm-1 for compound **16**; 420, 346, 327 cm-1 for compound **14**.

Compounds **5**, **18***,* **19**, and **20** were optimized by B3LYP method with 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p), and with density functional theory by using the BP86 hybrid functional with 30% HF exchange (B3P86-30%), and Stevens-Basch-Krauss pseudo potentials with polarized split valence basis sets (CEP-31G\*) (Stevens et al., 1984) and theoretical calculated wave numbers of electronic transitions for compounds **5**, **18***,* **19**, and **20** are reported in Tables 9 and 10. Very weak features with oscillator strengths below 0.25 were omitted.


Table 9. Experimental and theoretical UV assignments for compounds **18, 5**, **19***,* and **20** calculated by using TDB3LYP with the 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p), BP86-CEP-31G\* basis set

The UV visible spectral values, excitation energies, and ossillator strengths were calculated at TDB3LYP levels by using 6-31G(d,p), 6-311Gs(d,p), 6-311++G(d,p) basis sets and TDBP86- CEP-31G\* level for compounds **5**, **18***,* **19**, and **20**. There was an agreement between the UV calculations at the level of TDBP86-CEP-31G\* for ligands, and experimental results.

The C=N transitions due to n– for isatin-3-thiosemicarbazones were assigned as 2070 cm-1 (483 nm) of (Akinchan et al., 2002). This band was found to be 372, 373, 370, 370 nm for compounds **5**, **18***,* **19**, and **20**, respectively. At the level of TDBP86-CEP-31G\*, this band for compounds **5**, **18***,* **19**, and **20** was found at 382 nm, which arises from 3-1', 2-1', 3-1', and 3-1' transitions. The bands due to –\* transitions of semicarbazone group for isatin-3 thiosemicarbazone were between the range of 400-286 nm (Akinchan et al., 2002). Band at

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 47

Compound **11** - 254 268 288 296 360 434 6-31G(d,p) 249 361 364 436-441 457 6-311G(d,p) 251 363 365 436-439 453 CEP-31G 239 356-352 422-420 436 Compound **6** - 254 268 290 296 364 434 6-31G(d,p) 211 250 359 365 437 444 6-311G(d,p) 213-212 252 361 366 439-436 450 CEP-31G 241 355-350 435-423-420 Compound **9** 250 - 258 - 302 308 444 6-31G(d,p) 228 243-264 401-403 450 461-463 6-311G(d,p) 245 250-265 400-401 450-462 474-478 CEP-31G 240-234 254 388 438-428 461-457-453

Compound **10** - - 260 300 312 444 6-31G(d,p) 249-253-256 270 406-406 455 475-479 6-311G(d,p) 252-261 271 404-404 465 481-484

Table 11. Experimental and theoretical UV assignments for compounds **11**, **6**, **9**, and **10** calculated by using TDB3LYP with the 6-31G(d,p), 6-311G(d,p), BP86-CEP-31G basis set

Comp. **16** 254 262 296 374 450 635 842 6-31G(d,p) 251 - 346 363-374 408-419 659 729 311G(d,p) 255 266 342-308 365-355 423-412 657-617 - CEP-31G 248-244 293-261 345-344-300 387-384 473-445 606 - 6-311G(d,p)(1) - - 346-346-344 386-381 490-434-432 - - CEP-31G(1) - - 330-330 367-366 415-411 476 - Comp. **17**244 264 292 378 450 636 832 6-31G(d,p) 247-231 252 344 375-361 459-418-406 659 731 6-311G(d,p) 229-247 265 340-353-364 409-421 456 620-658 - CEP-31G 246-241-237 301-265 343-342-332 386-382 475-447 614 - 6-311G(d,p)(1) - - 386-382 403-392 486-418 - -

359-328-327

Comp. **14** - 260 300 414 435 636 826 6-31G(d,p) - 250-252-263 280-310 374-379-392 421-430 604-652 743

6-311G(d,p)(1) - - 406-342-341 447-420-419 510 - - CEP-31G(1) - 288 354 425-405-401 494 - - **[Ni(HICPT)2]** - 264 300 410 - 637 883 6-31G(d,p) 286-310 374 433 - - 747 6-311G(d,p) 309 310 374 384 666


306-311-368 368-392 432-421 622 663

298-287-265 370-321 413-410-397 486-448 614 -

<sup>236</sup>435-390 448-443 461-460

CEP-31G 260-248-241-

CEP-31(1) 253-248-242 263 366-363-


6-311G(d,p) - 253-262-270

239-236

CEP-31G 253-248-248-

305 nm at the level of TDBP86-CEP-31G\* was predicted for compounds **5**, **18***,* **19**, and **20**, which arises mainly from 4-1', transitions.

The UV transitions and their excitation energies and ossillator strengths for zinc (II) and nickel (II) complexes of compounds **5**, **18***,* **19**, and **20** were calculated by using TDB3LYP with the 6- 31G(d,p), 6-311G(d,p), BP86-CEP-31G basis sets. The transitions for nickel (II) complexes were calculated with both multiplicity states, 1 and 3, with two unpaired electrons. The results are summarized in Tables 11-14. The UV spectra, calculated with two unpaired electrons for nickel (II) complexes, were not in agreement with the experimental results. The band assigned at around 372, due to C=N transitions, were observed at 432, and 450 nm in the UV spectra of zinc (II) and nickel (II) complexes, respectively. Band at 434 nm (experimental) for compound **18** was found to be at 436 nm in the calculated of spectra of BP86-CEP-31G. Bands located around 360 nm in zinc (II) complexes and 374 nm in nickel (II) complexes due to ligand LMCT transition, suggested a metal–sulfur bond formation (Akinchan et al., 2002). Nickel (II) complexes showed three transitions around 450, belonging to transition 3A2g3T2g (F), 635 including transition A2g3T2g (F), and 842 in transition 3A2g3T1g (P), these transitions are characteristic of hexacoordinated nickel (II) complexes.


Table 10. TDB3LYP method with the 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p) basis sets and TDBP86-CEP-31G\* excitation energies in eV for compounds **18***,* **5**, **19***,* and **20**, and Oscillator Strengths (in Parenthesis)

305 nm at the level of TDBP86-CEP-31G\* was predicted for compounds **5**, **18***,* **19**, and **20**,

The UV transitions and their excitation energies and ossillator strengths for zinc (II) and nickel (II) complexes of compounds **5**, **18***,* **19**, and **20** were calculated by using TDB3LYP with the 6- 31G(d,p), 6-311G(d,p), BP86-CEP-31G basis sets. The transitions for nickel (II) complexes were calculated with both multiplicity states, 1 and 3, with two unpaired electrons. The results are summarized in Tables 11-14. The UV spectra, calculated with two unpaired electrons for nickel (II) complexes, were not in agreement with the experimental results. The band assigned at around 372, due to C=N transitions, were observed at 432, and 450 nm in the UV spectra of zinc (II) and nickel (II) complexes, respectively. Band at 434 nm (experimental) for compound **18** was found to be at 436 nm in the calculated of spectra of BP86-CEP-31G. Bands located around 360 nm in zinc (II) complexes and 374 nm in nickel (II) complexes due to ligand LMCT transition, suggested a metal–sulfur bond formation (Akinchan et al., 2002). Nickel (II) complexes showed three transitions around 450, belonging to transition 3A2g3T2g (F), 635 including transition A2g3T2g (F), and 842 in transition 3A2g3T1g (P), these transitions are

6-31G(d,p) 3.11(0.28)E2 3.80(0.35)E5 4.68(0.12)E9 4.98(0.07)E13 5.30(0.07)E16 5.66(0.09)E23 6-311G(d,p) 3.09(0.30)E2 3.80(0.35)E5 4.66(0.11)E9 5.26(0.07)E16 5.58(0.12)E22 5.91(0.10)E26 6-311++G(d,p) 3.04(0.30)E2 3.73(0.32)E5 4.59(0.09)E9 5.47(0.09)E26 5.54(0.07)E28 5.80(0.08)E39

6-31G(d,p) 3.05(0.26)E2 3.78(0.41)E5 4.65(0.11)E6 4.91(0.05)E9 5.26(0.11)E10 5.88(0.10)E18 6-311G(d,p) 3.04(0.28)E2 3.78(0.41)E5 4.63(0.11)E6 4.88(0.04)E9 5.21(0.11)E10 5.43(0.11)E11

6-311++G(d,p) 2.99(0.29)E2 3.71(0.39)E5 4.56(0.10)E6 4.79(0.04)E9 5.11(0.11)E12 5.75(0.08)E31 BP86-CEP-31G\* 3.24(0.40)E2 3.97(0.34)E5 4.83(0.13)E6 5.16(0.08)E8 5.46(0.10)E10 5.75(0.08)E31

6-31G(d,p) 3.10(0.27)E3 3.48(0.46)E4 4.88(0.22)E9 4.88(0.18)E10 4.97(0.06)E12 5.11(0.10)E15

6-311G(d,p) 3.06(0.34)E2 3.86(0.37)E5 4.69(0.16)E10 5.26(0.08)E16 5.51(0.06)E21 5.90(0.14)E25 6-311++G(d,p) 3.01(0.34)E2 3.79 0.34)E5 4.61(0.14)E10 4.84(0.05)E14 5.16(0.06)E18 5.37(0.04)E23

BP86-CEP-31G\* 3.24(0.41)E2 3.52 0.07)E3 4.06(0.29)E5 4.88(0.20)E9 5.21(0.08)E14 5.50(0.08)E17

6-31G(d,p) 2.80(0.06)E2 3.08(0.26)E3 3.47(0.49)E4 4.72(0.29)E9 4.81(0.08)E10 4.83(0.17)E11

6-311G(d,p) 2.90(0.06)E2 3.07(0.28)E3 3.47(0.48)E4 4.65(0.29)E9 4.80(024)E12 4.93(0.06)E13

6-311++G(d,p) 2.84(0.05)E2 3.03(0.28)E3 3.41(0.46)E4 4.60(0.28)E9 4.74(018)E12 4.90(0.10)E14

BP86-CEP-31G\* 3.17(0.12)E2 3.24(0.32)E3 3.66(0.42)E4 4.83(0.24)E9 4.88(013)E10 5.05(0.25)E11

Table 10. TDB3LYP method with the 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p) basis sets and TDBP86-CEP-31G\* excitation energies in eV for compounds **18***,* **5**, **19***,* and **20**, and Oscillator

4.86(0.14)E9 5.22(0.10)E11 5.51(0.06)E17 5.88(0.16)E21

5.84(0.09)E18

5.98(0.08)E26

5.80(0.16)E35

5.74(0.06)E18

5.96(0.10)E28

5.92(0.09)E28

5.93(0.10)E41

5.24(0.10)E13

which arises mainly from 4-1', transitions.

characteristic of hexacoordinated nickel (II) complexes.

4.01(0.26)E5

BP86-CEP-31G\* 3.28(0.36)E2 3.55(0.08)E3

Compound **18**

Compound **5**

Compound **19**

Compound **20**

Strengths (in Parenthesis)


Table 11. Experimental and theoretical UV assignments for compounds **11**, **6**, **9**, and **10** calculated by using TDB3LYP with the 6-31G(d,p), 6-311G(d,p), BP86-CEP-31G basis set


Quantum Chemical Calculations for some Isatin Thiosemicarbazones 49

CEP-31(1) 2.60(0.10)E10 2.98(0.14)E19 3.01(0.08)E20 3.37(0.18)E27 3.38(0.06)E28 3.75(0.15)E39

3.05(0.09)E13 3.29(0.15)E16 3.60(0.18)E22

3.03(0.10)E13 3.38(0.17)E18 3.54(0.12)E21

3.21(0.14)E12 3.24(0.10)E13 3.61(0.20)E17

3.14(0.08)E32

3.18(0.10)E30 3.06(0.19)E37 3.0(0.18)E38

3.16(0.13)E17 3.26(0.12)E19 3.31(0.11)E21

2.99(0.10)E13 3.15(0.16)E18 3.37(0.22)E23

3.12(0.12)E15 3.35(0.07)E16

6-31G(d,p) 1.66(0.08)E3 2.86(0.22)E11 3.30(0.16)E21 3.99(0.13)E34 4.32(0.13)E48 4.66(0.10)E63

311G(d,p) 1.86(0.06)E5 3.22(0.22)E18 3.30(0.16)E21 3.57(0.10)E23 3.99(0.13)E34 4.00(0.34)E37

3.14(0.08)E15 3.33(0.10)E16 3.86(0.16)E25

6-311G(d,p)(1) 2.42(0.10)E13 3.27(0.11)E19 2.91(0.24)E27 3.42(0.34)E28 3.04(0.08)E29 3.31(0.09)E33 CEP-31(1) 2.51(0.09)E10 3.51(0.09)E10 2.91(0.09)E21 3.06(0.36)E23 3.08(0.38)E24 3.04(0.06)E36

Table 14. TDB3LYP method with the 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p) basis sets and TDBP86-CEP-31G excitation energies in eV for compounds **16**, **17**, **14**, **15**, and Oscillator

Experimental and calculated theoretical NMR parameters for compounds **5**, **18***,* **19**, and **20** were shown in Table 15. Geometrical optimization of studied ligands were performed at the level of B3LYP/6-311G(d,p), and B3LYP/6-311++G(d,p). NMR Chemical shifts were predicted from Gauge-Independent Atomic Orbital (GIAO) calculations at the same level of theory at DMSO solution with both gas phase optimization and DMSO optimization. Theoretically calculated 1H-NMR parameters are generally in agreement with experimental results, except deviation in N8-H of isatin ring, and N14-H of thiosemicarbazone group.

6-311G(d,p)(1) 2.43(0.10)E13 3.26(0.10)E19 2.95(0.25)E27 2.96(0.29)E28 3.05(0.12)E29 CEP-31(1) 2.51(0.09)E10 2.91(0.09)E21 3.06(0.36)E23 3.09(0.38)E24 3.50(0.06)E36 4.31(0.11)E58

3.62(0.18)E18 3.73(0.09)E20 4.11(0.08)E27

3.27(0.05)E36 3.20(0.06)E38

3.20(0.06)E62 3.06(0.17)E67

4.00(0.11)E33 4.42(0.12)E50 4.70(0.09)E61

3.98(0.09)E33 4.05(0.09)E37

3.85(0.13)E25 4.15(0.11)E29 4.30(0.14)E33

4.15(0.11)E29 4.28(0.14)E31 4.61(0.07)E41

Compound **17**

Compound **14**

Compound **15**

(1) triplet state

Strengths (in Parenthesis)

**3.5 NMR spectra** 

6-31G(d,p) 1.70(0.06)E3

311G(d,p) 1.88(0.04)E3

CEP-31(1) 3.24(014)E19

6-31G(d,p) 1.67(0.08)E3

311G(d,p) 1.87(0.07)E3

CEP-31 2.02(0.10)E5

1.88(0.02)E4

1.99(0.06)E4

3.19(008)E20

1.90(0.02)E5 2.05(0.01)E7

1.99(0.04)E4

2.55(0.07)E8

CEP-31 2.02(0.10)E5 2.56(0.08)E8

6-311G(d,p)(1) 2.55(0.07)E15 2.96(0.06)E26 3.07(0.08)E30

CEP-31 2.02(0.08)E5 2.61(0.06)E8

2.70(0.06)E9 2.96(0.13)E11

2.71(0.06)E9 3.02(013)E11

2.77(0.06)E9

3.19(0.11)E25 3.41(0.05)E28

2.88(0.21)E11 2.95(0.09)E13

2.72(0.06)E9 2.88(0.19)E12

2.77(0.05)E9 2.99(0.16)E11 3.02(0.32)E12

3.00(0.17)E11 3.02(0.34)E12 3.76(0.20)E40

5.41(0.10)E69

5.14(0.13)E49 5.21(0.14)E52

4.72(0.08)E62 4.90(0.33)E73

5.13(0.08)E61 5.16(0.16)E62 5.23(0.35)E68

4.70(0.12)E67

4.95(0.10)E57 4.99(0.11)E59 5.17(0.31)E65

4.67(0.09)E37 5.03(0.42)E46

3.62(0.22)E47 3.64(0.77)E48

4.99(0.06)E71 5.10(0.17)E76

4.91(0.12)E72 4.97(0.19)E75

4.29(0.11)E44 4.59(0.10)E57

4.67(0.10)E43 4.89(0.30)E51 4.99(0.12)E56 4.99(0.17)E57

4.83(0.06)E49 4.85(0.12)E51 4.87(0.36)E52

4.91(0.23)E54 5.00(0.18)E57 5.34(0.17)E67

3.64(0.11)E24 4.67(0.18)E47 5.02(0.27)E57


(1) triplet state

Table 12. Experimental and theoretical UV assignments for compounds **16**, **17**, **14**, and **15** calculated by using TDB3LYP with the 6-31G(d,p), 6-311G(d,p), BP86-CEP-31G basis set


Table 13. TDB3LYP method with the 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p) basis sets and TDBP86-CEP-31G excitation energies in eV for compounds **11**, **6***,* **9**, **10**, and Oscillator Strengths (in Parenthesis)



(1) triplet state

48 Quantum Chemistry – Molecules for Innovations

6-311G(d,p)(1) - - 406-374-370 448-425-422 511 - - CEP-31G(1) - 288 405-401-354 425 493 - -

Table 12. Experimental and theoretical UV assignments for compounds **16**, **17**, **14**, and **15** calculated by using TDB3LYP with the 6-31G(d,p), 6-311G(d,p), BP86-CEP-31G basis set

6-31G(d,p) 3.11(0.28)E2 3.80(0.35)E5 4.68(0.12)E9 4.98(0.07)E13 5.30(0.07)E16 5.66(0.09)E23 6-311G(d,p) 3.09(0.30)E2 3.80(0.35)E5 4.66(0.11)E9 5.26(0.07)E16 5.58(0.12)E22 5.91(0.10)E26 6-311++G(d,p) 3.04(0.30)E2 3.73(0.32)E5 4.59(0.09)E9 5.47(0.09)E26 5.54(0.07)E28 5.80(0.08)E39 CEP-31G 3.24(0.41)E2 4.06(0.29)E5 4.88(019)E9 5.20(0.08)E14 5.50(0.08)E17 5.74(0.06)E18

6-31G(d,p) 3.05(0.26)E2 3.78(0.41)E5 4.65(0.11)E6 4.91(0.05)E9 5.26(0.11)E10 5.88(0.10)E18 6-311G(d,p) 3.04(0.28)E2 3.78(0.41)E5 4.63(0.11)E6 4.88(0.04)E9 5.21(0.11)E10 5.43(0.11)E11

6-311++G(d,p) 2.99(0.29)E2 3.71(0.39)E5 4.56(0.10)E6 4.79(0.04)E9 5.11(0.11)E12 5.75(0.08)E31 CEP-31G 3.24(0.40)E2 3.97(0.34)E5 4.83(0.13)E6 5.16(0.08)E8 5.46(0.10)E10 5.75(0.08)E31

6-31G(d,p) 3.10(0.27)E3 3.48(0.46)E4 4.88(0.22)E9 4.88(0.18)E10 4.97(0.06)E12 5.11(0.10)E15

6-311G(d,p) 3.06(0.34)E2 3.86(0.37)E5 4.69(0.16)E10 5.26(0.08)E16 5.51(0.06)E21 5.90(0.14)E25 6-311++G(d,p) 3.01(0.34)E2 3.79 0.34)E5 4.61(0.14)E10 4.84(0.05)E14 5.16(0.06)E18 5.37(0.04)E23

CEP-31G 3.24(0.41)E2 3.52 0.07)E3 4.06(0.29)E5 4.88(0.20)E9 5.21(0.08)E14 5.50(0.08)E17

6-31G(d,p) 2.88(0.06)E2 3.08(0.26)E3 3.47(0.49)E4 4.72(0.29)E9 4.81(0.08)E10 4.83(0.17)E11

6-311G(d,p) 2.90(0.06)E2 3.07(0.28)E3 3.47(0.48)E4 4.65(0.29)E9 4.80(024)E12 4.93(0.06)E13

6-311++G(d,p) 2.84(0.05)E2 3.03(0.28)E3 3.41(0.46)E4 4.60(0.28)E9 4.74(018)E12 4.90(0.10)E14

CEP-31G 3.17(0.12)E2 3.24(0.32)E3 3.66(0.42)E4 4.83(0.24)E9 4.88(013)E10 5.05(0.25)E11

Table 13. TDB3LYP method with the 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p) basis sets and TDBP86-CEP-31G excitation energies in eV for compounds **11**, **6***,* **9**, **10**, and Oscillator

2.95(0.12)E11 3.31(015)E13 3.40(0.14)E16

2.93(0.11)E12 3.01(011)E13 3.39(0.26)E18

3.20(013)E12 3.22(012)E13

3.21(0.12)E28 3.24(0.07)E30

2.79(0.07)E9

3.41(0.24)E19

3.49(0.09)E21

3.58(0.25)E17 3.60(0.18)E18

3.58(0.19)E36 3.58(0.08)E37

394-371 413-409 485 - 613

5.84(0.09)E18

5.98(0.08)E26

5.80(0.16)E35

5.74(0.06)E18

5.96(0.10)E28

5.92(0.09)E28

5.93(0.10)E41

5.24(0.10)E13

4.65(0.26)E60 4.92(0.21)E76

4.74(0.08)E45 4.98(0.18)E53 5.07(0.30)E58

3.58(0.10)E22 4.92(0.21)E76

3.60(0.10)E39 3.82(0.10)E51

3.62(0.11)E24 4.03(0.08)E33

4.12(0.08)E27 4.23(0.10)E29

321-294- 289-268

CEP-31G 256-255-

(1) triplet state

Compound **11**

Compound **6**

Compound **9**

Compound **10**

Compound **16**

Strengths (in Parenthesis)

6-31G(d,p) 1.70(0.06)E3

311G(d,p) 1.88(0.03)E3

1.88(0.02)E4

2.01(0.07)E4

6-311G(d,p)(1) 2.53(0.06)E13 2.86(0.15)E19 2.87(007)E20

CEP-31 2.04(0.08)E5 2.62(0.06)E8

248-239

Table 14. TDB3LYP method with the 6-31G(d,p), 6-311G(d,p), 6-311++G(d,p) basis sets and TDBP86-CEP-31G excitation energies in eV for compounds **16**, **17**, **14**, **15**, and Oscillator Strengths (in Parenthesis)

#### **3.5 NMR spectra**

Experimental and calculated theoretical NMR parameters for compounds **5**, **18***,* **19**, and **20** were shown in Table 15. Geometrical optimization of studied ligands were performed at the level of B3LYP/6-311G(d,p), and B3LYP/6-311++G(d,p). NMR Chemical shifts were predicted from Gauge-Independent Atomic Orbital (GIAO) calculations at the same level of theory at DMSO solution with both gas phase optimization and DMSO optimization. Theoretically calculated 1H-NMR parameters are generally in agreement with experimental results, except deviation in N8-H of isatin ring, and N14-H of thiosemicarbazone group.

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 51

C1-H 7.39 7.63 7.46 7.87 7.64 7.12 C2-H 7.15 7.29 7.21 7.51 7.33 7.38 C3-H 6.83 7.14 6.78 7.29 7.18 6.95 C4-H 7.69 7.84 7.71 8.03 7.88 7.78 C25-H 7.47 7.56 7.58 7.86 7.58 7.63 C26-H 7.47 7.56 7.58 7.86 7.81 7.63 C27-H 7.61 7.80 7.67 8.04 7.80 7.44 C29-H 7.61 7.80 7.67 8.04 7.81 7.44 C31-H 7.58 7.79 7.56 7.93 7.58 7.28 N8-H 6.22 6.86 6.46 7.89 6.94 10.83 N12-H 12.40 12.32 12.61 12.45 12.55 12.81 N14-H 8.65 9.08 8.80 9.45 9.03 11.26

C1-H 7.43 7.63 7.34 7.73 7.65 7.12 C2-H 9.42 7.33 7.22 7.52 7.37 7.38 C3-H 6.85 7.14 6.81 7.30 7.17 6.95 C4-H 7.78 7.95 7.88 8.11 7.98 7.77 C26-H 6.80 7.24 6.90 7.44 7.24 7.67 C29-H 7.33 7.55 7.43 7.87 7.55 7.49 C27-H 7.46 7.54 7.55 7.85 7.57 7.49 C25-H 9.91 9.75 9.98 9.84 9.77 7.67 N8-H 6.25 6.86 6.54 7.94 6.94 10.86 N12-H 12.40 12.33 12.71 12.58 12.51 12.85 N14-H 9.42 9.77 9.76 10.10 9.74 11.27

a Optimisation were calculated in the gas phase and Theoretical NMR shifting were calculated in the

by using B3LYP with the 6-311G(d,p), 6-311++G(d,p) basis set for gas and DMSO phase

of compounds **5**, **18***,* **19**, and **20** disappeared in their corresponding complexes.

N12 belong to thiosemicarbazone group in its complex form.

Table 15. Experimental and theoretical NMR shifting for compounds **18**, **5**, **19**, and **20** calculated

The proton signal of N8-H group seen at 9.77, 8.85, 10.83, 10.88, respectively, in the 1H-NMR spectrum for compounds **5**, **18***,* **19**, and **20,** also appeared in the spectrum of their zinc (II) complexes at 10.81, 10.80, 11.01, and 11.06, respectively. The upfield shift was due to the lack of intermolecular hydrogen bonding in its corresponding complex (Akinchan et al., 2002). A stronger hydrogen-bond interaction will shorten the O-H distance, will elongate the N–H distance, and will also cause a significant deshielding of the proton leading to a further downfield NMR signal (De Silva et al., 2007). The peak due to N12-H in the 1H-NMR spectra

The experimental and theoretical NMR results of compounds **11**, **6**, **9**, and **10** are shown in Table 16. Geometrical optimizations of above mentioned studied complexes were performed by using the B3LYP method, and 6-31G(d,p), 6-311G(d,p) standard basis sets at the gas phase, and DMSO solution. The calculated peak, due to N12-H in the 1H-NMR spectra of compounds **5**, **18***,* **19**, and **20** disappears in their corresponding zinc (II) complexes, as the calculation was performed by considering the corresponding ligand, deprotonated from

Compound **19**

Compound **20**

DMSO solution

The correlations between theoretical, and experimental NMR results, calculated with B3LYP/6-311, B3LYP/6-311++ level of theory are 97.6%, and 98.2% and at gas phase; 96.9%, 96.4%, in DMSO solution (but optimization was in gas phase), and at the B3LYP/6-311++ level of theory 96.9% in DMSO solution (and also optimisation in DMSO solution) for compound **18***.* Although the experimental proton signal of N12-H of isatin group for compounds **5**, **18***,* **19**, and **20** was 12.64, 12.57, 12.81 and 12.85, and theoretical one was 12.37, 12.21, 12.55, 12.51 in the DMSO solution at the level of B3LYP/6-311++G/dip) theory.


The correlations between theoretical, and experimental NMR results, calculated with B3LYP/6-311, B3LYP/6-311++ level of theory are 97.6%, and 98.2% and at gas phase; 96.9%, 96.4%, in DMSO solution (but optimization was in gas phase), and at the B3LYP/6-311++ level of theory 96.9% in DMSO solution (and also optimisation in DMSO solution) for compound **18***.* Although the experimental proton signal of N12-H of isatin group for compounds **5**, **18***,* **19**, and **20** was 12.64, 12.57, 12.81 and 12.85, and theoretical one was 12.37, 12.21, 12.55, 12.51 in the DMSO solution at the level of B3LYP/6-311++G/dip) theory.

6-311-G(d,p) 6-311++G(d,p) 6-311++G(d,p) Exp,

C1-H 7.30 7.53 7.24 7.66 7.55 7.01 C2-H 6.99 7.13 7.01 7.31 7.17 7.31 C3-H 6.76 7.08 6.78 7.30 7.11 6.91 C4-H 7.38 7.49 7.53 7.63 7.53 7.63 C21-H 4.53 4.51 4.67 4.71 4.52 4.86

C25-H 7.66 7.78 7.75 8.06 7.80 7.32-7.36 C26-H 7.66 7.78 7.75 8.05 7.80 7.32-7.36 C27-H 7.62 7.76 7.75 8.05 7.77 7.32-7.36 C29-H 7.62 7.76 7.72 8.05 7.77 7.32-7.36 C31-H 7.58 7.74 7.54 7.88 7.75 7.23 N8-H 6.16 6.80 6.43 7.86 6.88 9.77 N12-H 12.27 12.17 12.62 12.46 12.37 12.64 N14-H 6.84 7.23 7.17 7.44 7.16 11.18

C1-H 7.37 7.60 7.40 7.82 7.62 7.10

C2-H 7.14 7.30 7.18 7.50 7.33 7.36 C3-H 6.80 7.11 6.77 7.27 7.14 6.93 C4-H 7.66 7.81 7.74 7.98 7.85 7.74 C24-H 4.42 4.22 4.50 4.41 4.35 4.19 C26-H 2.36 2.12 2.39 2.18 1.98 1.92 C26-H 0.98 1.23 1.00 1.27 1.31 1.54-1.44 C27-H 1.53 1.50 1.53 1.52 1.53 1.35-1.26 C27-H 1.77 1.81 1.79 1.85 1.84 1.77 C31-H 1.25 1.34 1.29 1.39 1.33 1.14 C31-H 1.69 1.68 1.70 1.71 1.70 1.64 C29-H 1.54 1.52 1.55 1.56 1.54 1.35-1.26 C29-H 1.83 1.88 1.82 1.88 1.88 1.77 C25-H 1.98 1.96 2.03 2.04 1.92 1.92 C25-H 1.31 1.55 1.36 1.60 1.45 1.54-1.44 N8-H 6.18 6.81 6.47 7.90 6.89 8.85 N12-H 12.19 12.05 12.41 12.23 12.21 12.57 N14-H 7.06 7.55 7.28 7.70 7.44 11.20

Atoms gas DMSOa gas DMSOa DMSO

C21-H 4.53 4.51 4.67 4.71 4.52

Compound **18**

Compound **5**


a Optimisation were calculated in the gas phase and Theoretical NMR shifting were calculated in the DMSO solution

Table 15. Experimental and theoretical NMR shifting for compounds **18**, **5**, **19**, and **20** calculated by using B3LYP with the 6-311G(d,p), 6-311++G(d,p) basis set for gas and DMSO phase

The proton signal of N8-H group seen at 9.77, 8.85, 10.83, 10.88, respectively, in the 1H-NMR spectrum for compounds **5**, **18***,* **19**, and **20,** also appeared in the spectrum of their zinc (II) complexes at 10.81, 10.80, 11.01, and 11.06, respectively. The upfield shift was due to the lack of intermolecular hydrogen bonding in its corresponding complex (Akinchan et al., 2002). A stronger hydrogen-bond interaction will shorten the O-H distance, will elongate the N–H distance, and will also cause a significant deshielding of the proton leading to a further downfield NMR signal (De Silva et al., 2007). The peak due to N12-H in the 1H-NMR spectra of compounds **5**, **18***,* **19**, and **20** disappeared in their corresponding complexes.

The experimental and theoretical NMR results of compounds **11**, **6**, **9**, and **10** are shown in Table 16. Geometrical optimizations of above mentioned studied complexes were performed by using the B3LYP method, and 6-31G(d,p), 6-311G(d,p) standard basis sets at the gas phase, and DMSO solution. The calculated peak, due to N12-H in the 1H-NMR spectra of compounds **5**, **18***,* **19**, and **20** disappears in their corresponding zinc (II) complexes, as the calculation was performed by considering the corresponding ligand, deprotonated from N12 belong to thiosemicarbazone group in its complex form.

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 53

N8-H 8.20 7.25 8.59 7.55 11.06 N14-H 7.55 6.15 8.28 6.88 10.74 a Optimisation were calculated in the gas phase and Theoretical NMR shifting were calculated in the

All the compounds **1**-**16** were tested against the two Gram-positive bacterial strains i.e. *Staphlococcus aureus* and *Bacillus subtilus*, and four Gram-negative bacterial strains i.e. *Escherichia coli. Shigella flexnari*, *Pseudomonas aeruginosa,* and *Salmonella typhi*, according to the literature protocol (Becke, 1993). The results were compared with the standard drug

> Shigella flexnari

Table 17. Antibacterial activity for Escherichia coli, Shigella flexnari, Pseudomonas

1 00 00 00 00 00 00 2 00 00 00 00 00 00 3 00 00 00 00 00 00 4 00 00 00 00 00 00 5 00 00 00 00 00 00 6 00 00 00 00 00 00 7 00 00 00 00 00 00 8 00 00 00 00 00 00 9 00 00 00 00 00 00 10 00 00 00 00 00 00 11 00 00 00 00 00 00 12 00 00 00 00 00 00 13 00 00 00 00 00 00 14 00 00 00 00 00 00 15 00 00 00 00 00 00 16 00 00 00 00 00 00 SD\* Imipenem 30 33 27 33 24 25

Staphlococcus aureus

Pseudomonas aeruginosa

Salmonella typhi

Table 16. Experimental and theoretical NMR shifting for compounds **11**, **6**, **9**, and **10** calculated by using B3LYP with the 6-31G(d,p), 6-311G(d,p) basis set for gas and DMSO

7.03-8.08

C1-H 7.61 7.22 7.81 7.43

C2-H 6.92 6.74 7.21 6.82 C3-H 7.13 6.59 7.32 6.97 C4-H 7.54 7.70 8.01 7.64 C25-H 7.43 6.77 7.51 7.15 C29-H 7.67 7.29 7.83 7.48 C27-H 7.79 7.63 7.97 7.65 C26-H 10.09 10.21 10.28 10.13

Compound **10**

DMSO solution

Compound Name

**3.6 Antibacterial activity** 

imipenem and shown in Table 17.

aeruginosa, and Salmonella typhi

Escherichia coli

Bacillus subtilus

phase



a Optimisation were calculated in the gas phase and Theoretical NMR shifting were calculated in the DMSO solution

Table 16. Experimental and theoretical NMR shifting for compounds **11**, **6**, **9**, and **10** calculated by using B3LYP with the 6-31G(d,p), 6-311G(d,p) basis set for gas and DMSO phase

#### **3.6 Antibacterial activity**

52 Quantum Chemistry – Molecules for Innovations

6-311G(d,p) 6-31G(d,p) 6-311G(d,p) Experimental

C21-H 6.15 6.41 6.25 - 4.76

N8-H 7.38 5.98 8.11 - 10.81 N14-H 6.33 5.33 6.91 - 9.26

6.90-8.30 C2-H 6.73 6.73 7.17 6.85

N8-H 5.97 5.97 8.06 6.69 10.80 N14-H 5.30 5.30 6.83 5.65 8.77

N8-H 8.26 8.63 7.63 7.63 11.01 N14-H 7.55 8.27 6.90 6.90 10.68

6.95-7.40

1.15-2.34

7.01-8.11

Atoms gas DMSOa gas DMSO

C1-H 7.63 7.21 7.79 -

C2-H 6.97 6.84 7.23 - C3-H 7.11 6.55 7.27 - C4-H 7.53 7.68 8.02 - C25-H 7.80 7.77 7.97 - C29-H 7.95 7.66 8.09 - C31-H 7.84 7.53 7.99 - C27-H 7.86 7.54 8.01 - C22-H 7.78 7.47 7.88 -

C21-H 4.17 4.00 4.30 -

C1-H 7.14 7.14 7.73 7.38

C3-H 6.51 6.51 7.23 6.89 C4-H 7.43 7.43 7.82 7.43 C24-H 4.80 4.80 4.98 4.64

C26-H 2.41 2.41 2.34 2.08 C26-H 1.05 1.05 1.52 1.26 C27-H 1.69 1.69 1.96 1.76 C27-H 1.72 1.72 1.81 1.51 C31-H 1.69 1.69 1.87 1.69 C31-H 1.25 1.25 1.59 1.31 C29-H 1.82 1.82 2.06 1.90 C29-H 1.64 1.64 1.85 1.59 C25-H 1.24 1.24 1.69 1.40 C25-H 2.03 2.03 2.21 2.06

C1-H 7.61 7.79 7.43 7.43

C2-H 6.93 7.22 6.84 6.84 C3-H 7.13 7.31 6.98 6.98 C4-H 7.60 8.08 7.60 7.60 C26-H 7.49 7.51 7.24 7.24 C29-H 7.83 7.97 7.67 7.67 C31-H 7.56 7.76 7.43 7.43 C27-H 7.94 8.11 7.83 7.83 C25-H 10.10 10.22 10.14 10.14

Compound **11**

Compound **6**

Compound **9**

All the compounds **1**-**16** were tested against the two Gram-positive bacterial strains i.e. *Staphlococcus aureus* and *Bacillus subtilus*, and four Gram-negative bacterial strains i.e. *Escherichia coli. Shigella flexnari*, *Pseudomonas aeruginosa,* and *Salmonella typhi*, according to the literature protocol (Becke, 1993). The results were compared with the standard drug imipenem and shown in Table 17.


Table 17. Antibacterial activity for Escherichia coli, Shigella flexnari, Pseudomonas aeruginosa, and Salmonella typhi

Quantum Chemical Calculations for some Isatin Thiosemicarbazones 55

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## **3.7 Antifungal activity**

All the compounds **1-16** were also tested against *Candida albicans*, *Aspergillus falvus*, *Microsporum canis*, *Fusarium solani*, and *Candida galbrata*, according to the literature protocol (Lee et al., 1988) and found that compounds showed a varying degree of percentage inhibition. These results were compared with the standard drugs miconazole and amphotericin B, as shown in Table 18.


Table 18. Antifungal activity for Candida albicans, Aspergillus falvus, Microsporum canis, Fusarium solani, and Candida galbrata

Compounds **1***,* **14***,* **16***,* **8***,* and **13** exhibited activity against *Microsporum canis* with 50, 50, 50, 80, and 70% inhibition, respectively. Compounds **4***,* **12***,* and **13** showed a moderate inhibition against *Fusarium solani* with a percentage inhibition of 40, 40, and 40%, respectively. Compound **5** demonstrated activity an against *Aspergillus flavus* (40% inhibition). Compound **10** was found to be active against Candia albicans with 40% inhibition.

Table 18 shows results of antifungal assay on compounds **1***-***16** (concentration used 200 g/mL of DMSO, and Percentage Inhibition). All the compounds in this series showed nonsignificant activity against all the bacteria.

## **4. Acknowledgement**

The financial support for this study was provided by the TUBİTAK Fund (Project Number: 108T974), and the High Education Commission of Pakistan.

## **5. References**

Agrawal, K.C. & Sartorelli, A.C. (1978). The chemistry and biological activity of α-(N) heterocyclic carboxaldehyde Thiosemicarbazones. *Prog. Med. Chem.,* Vol. 15, pp. (321-356), ISSN: 0079-6468.

All the compounds **1-16** were also tested against *Candida albicans*, *Aspergillus falvus*, *Microsporum canis*, *Fusarium solani*, and *Candida galbrata*, according to the literature protocol (Lee et al., 1988) and found that compounds showed a varying degree of percentage inhibition. These results were compared with the standard drugs miconazole and

Compound Name **1 2 3 4 5 6 7 8** SD C. albicans 0 0 0 0 0 0 0 0 110 A. flavus 20 0 20 0 40 0 0 0 20 M. canis 50 60 00 60 30 0 0 80 98 F. Solani 20 0 30 40 10 0 25 30 73 C. glabrata 0 0 0 0 0 0 0 0 101

Compound Name **9 10 11 12 13 14 15 16** SD C. albicans 0 40 0 0 0 0 0 0 110 A. flavus 30 0 20 0 20 0 0 0 20 M. canis 20 0 20 20 70 50 20 50 98 F. Solani 05 0 0 40 40 20 0 0 73 C. glabrata 0 0 0 0 0 0 0 0 101 Table 18. Antifungal activity for Candida albicans, Aspergillus falvus, Microsporum canis,

Compounds **1***,* **14***,* **16***,* **8***,* and **13** exhibited activity against *Microsporum canis* with 50, 50, 50, 80, and 70% inhibition, respectively. Compounds **4***,* **12***,* and **13** showed a moderate inhibition against *Fusarium solani* with a percentage inhibition of 40, 40, and 40%, respectively. Compound **5** demonstrated activity an against *Aspergillus flavus* (40% inhibition).

Table 18 shows results of antifungal assay on compounds **1***-***16** (concentration used 200 g/mL of DMSO, and Percentage Inhibition). All the compounds in this series showed non-

The financial support for this study was provided by the TUBİTAK Fund (Project Number:

Agrawal, K.C. & Sartorelli, A.C. (1978). The chemistry and biological activity of α-(N)-

heterocyclic carboxaldehyde Thiosemicarbazones. *Prog. Med. Chem.,* Vol. 15, pp.

Compound **10** was found to be active against Candia albicans with 40% inhibition.

**3.7 Antifungal activity** 

amphotericin B, as shown in Table 18.

Fusarium solani, and Candida galbrata

significant activity against all the bacteria.

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**4. Acknowledgement** 

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**4** 

*Ukraine* 

**Elementary Molecular Mechanisms of** 

**A Novel Quantum-Chemical Insight** 

**into the Classical Understanding** 

*"State Key Laboratory of Molecular and Cell Biology", Kyiv, 3Department of Molecular Biology, Biotechnology and Biophysics,* 

*1Department of Molecular and Quantum Biophysics,* 

*Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv,* 

*2Research and Educational Center* 

**the Spontaneous Point Mutations in DNA:** 

Ol'ha O. Brovarets'1,2,3, Iryna M. Kolomiets'1 and Dmytro M. Hovorun1,2,3

*Institute of High Technologies, Taras Shevchenko National University of Kyiv, Kyiv,* 

DNA replication is an amazing biological phenomenon that is essential to the continuation of life (Kornberg & Baker, 1992). Faithful replication of DNA molecules by DNA polymerases is essential for genome integrity and stable transmission of genetic information in all living organisms. Although DNA replicates with immensely high fidelity, upon assembly of millions of nucleotides a DNA polymerase can make mistakes that are a major source of DNA mismatches. The overall accuracy and error spectrum of a DNA polymerase are determined mainly by three parameters: the nucleotide selectivity of its active site, its mismatch extension capacity, and its proofreading ability (Beard & Wilson, 1998, 2003; Joyce & Benkovic, 2004). Yet, natural and exogenous sources of DNA damage result in a variety of DNA modications, the most common including nucleobase oxidation (Nakabeppu et al., 2007), alkylation (Drabløs et al., 2004) and deamination (Ehrlich et al., 1986; Kow, 2002;

Depending on the type of mismatch and the biological context of its occurrence, cells must apply appropriate strategies of postreplication repair to avoid mutation (Kunz et al., 2009). However, some replication errors make it past these mechanisms, thus becoming permanent

Mutations are stable, heritable alterations of the genetic material, namely DNA (Friedberg et al., 2006). They are an important contributor to human aging, metabolic and degenerative disorders, cancer, and cause heritable diseases, at the same time they are the kindling factor for biological evolution of living things. Beyond the individual level, perhaps the most dramatic effect of mutation relates to its role in evolution; indeed, without mutation,

**1. Introduction** 

Labet et al., 2008).

mutations after the next cell division.

