2. Experimental

[18–20]. Schiff bases can be regarded as promising antimicrobial agents. For example, N-(salicylidene)-2-hydroxyaniline proved efficiency against Mycobacterium tuberculosis H37Rv, exhibiting an MIC value of 8μg/mL [21]. The 5-chloro-salicylaldehyde-Shiff base derivatives are efficient against Pseudomonas fluorescence (MIC=2.5–5.2μg/mL), Escherichia coli (MIC=1.6–5.7μg/mL), Bacillus subtilis (MIC=1.8μg/mL), and Staphylococcus aureus (MIC=1.6 and 3.1μg/mL), respectively, while the MIC values for the reference drug kanamycin against the same bacterial strains were 3.9μg/mL [22]. Some of the isatin-derived Schiff bases have shown antibacterial activity against Escherichia coli NCTC 10418 (MIC=2.4μg/mL), Vibrio cholerae non-01(MIC=0.3μg/mL), Enterococcus faecalis (MIC=1.2μg/mL), and Proteus shigelloides (MIC=4.9 μg/mL). The MIC values for the reference drug sulfamethoxazole against the same bacterial strain were in the range of 312–5000μg/mL. Therefore, these compounds were proven to be 1040-, 1040-, 4160-, and 1020-fold more potent than sulfamethoxazole [23, 24]. The studies run on the Schiff bases, derived from the isoniazid have allowed to identify a compound which has turned out to have a therapeutical effectiveness and safety, that is, 4000 times higher than that of isoniazid [25].

The morpholine-derived Schiff bases was effective against Staphylococcus aureus (MIC=20μg/mL), Micrococcus luteus (MIC=32μg/mL), Streptococcus epidermidis (MIC=17μg/mL), Bacillus cereus

Schiff bases with a 2,4-dichloro-5-fluorophenyl moiety completely inhibited the growth of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. MIC values for these compounds varied from 6.3 to 12.5μg /mL, which are comparable to those obtained for the reference drug ciprofloxacin [26]. Lately, within the last couple of years, a special attention has been paid to the chemistry of the metal complexes of the Schiff bases. This is due to the chemical stability of the complexes as well as to the possibility of using them in the most varied fields. To a great extent, remarkable successes, in this field, have been obtained due to the various synthesis methods of the complexes. Recent research focuses more and more on the synthesis of complexes of the transitional metals with ligands of Schiff-base type, as a result of the biological properties which they have. In many cases, the conclusion has been that, through the coordination of the Schiff bases, to the metal ions, which are present in the biological systems, the biological activity of the respective Schiff base increases. A large number of Schiff bases and the corresponding metal complexes have proven antibacterian, antifungal, antitumor, and antileukemia activity [27–29]. Ever since it was synthesized [30], antipyrine (1-fenil-2,3-dimetil-5-pirazolona) has enjoyed a lot of attention due to its analgesic and antipyretic properties. The discovery of these properties has allowed for deeper research on antipyrine and its derivatives. Thus, 4-amino-2,3-dimethyl-1 phenyl-3-pyrazolin-5-one (4-aminoantipyrine) was discovered, a derivative with analgesic action, antipyretic, anti-inflammatory, antibacterian, and antineoplastic [31, 32]. The derivatives of 4 aminoantipyrine are used in the synthesis of azo-colorant, in analytical chemistry for spectrophotometric determination of metal ions [33], in pharmacology, as an effective antitumor [34], analgesic [35], antiviral [36], anti-inflammatory [37], anticancer [38], and antimicrobial drugs [39–42].

Lately, the research has been conducted in order to get metal complexes with a wide range of biological activities and with the lowest level of toxicity. In this work, the synthesis of some complexes with base Schiff ligands is presented, derived from 4-aminoantipyrine and in vitro

(MIC=21μg/mL), and Escherichia coli (MIC=16μg/mL).

66 Descriptive Inorganic Chemistry Researches of Metal Compounds

research of their antibacterial activities.

### 2.1. Metal complexes with aminoantipyrine Schiff bases: structure and methods of synthesis

Complexes of Cu(II), Co(II), Ni(II), Zn(II), Mn(II), VO(II), and Fe(III) were prepared by direct reaction between Schiff base ligand and the corresponding metal salts.

The next Schiff bases were synthesized:


#### 2.1.1. Synthesis of the complexes with HL1–<sup>5</sup> ligands

The metal complexes with these Schiff bases are obtained by adding a methanolic or ethanolic ligand solution to a solution of metal salt, in a molar ratio L:M=2:1 [43, 44] or 1:1 [45–47]. The mixture of reaction is refluxed for 2–5h or stirring for 12h. The precipitate is obtained that is filtered, washed with ether, methanol or ethanol, and dried in vacuo (Figures 1–4).

M2+ = Cu2+, Ni2+, Co2+, Mn2+, Zn2+,Cd2+, Hg2+, VO2+, UO2 2+, ZrO2+

Figure 1. Scheme of synthesis of complexes with ligand HL1 .

n = 3 for M = Cr(III) and n = 2 for M = Cu(II), Co(II), Mn(II), Ni(II)

Figure 2. Scheme of synthesis of complexes with ligand HL2 .

Figure 3. Scheme of synthesis of complexes with ligand HL4 .

Transition Metal Complexes with Antipyrine‐Derived Schiff Bases: Synthesis and Antibacterial Activity http://dx.doi.org/10.5772/67584 69

Figure 4. Scheme of synthesis of complexes with ligand HL5 .

2.1.1. Synthesis of the complexes with HL1–<sup>5</sup> ligands

68 Descriptive Inorganic Chemistry Researches of Metal Compounds

Figure 1. Scheme of synthesis of complexes with ligand HL1

Figure 2. Scheme of synthesis of complexes with ligand HL2

Figure 3. Scheme of synthesis of complexes with ligand HL4

The metal complexes with these Schiff bases are obtained by adding a methanolic or ethanolic ligand solution to a solution of metal salt, in a molar ratio L:M=2:1 [43, 44] or 1:1 [45–47]. The mixture of reaction is refluxed for 2–5h or stirring for 12h. The precipitate is obtained that is

.

.

CH3 CH2 OH

.

refluxed 3h

M = Cu2+, Co2+, Ni2+, Zn2+

MCl n Cl 2 / CrCl3

M2+ = Cu2+, Ni2+, Co2+, Mn2+, Zn2+,Cd2+, Hg2+, VO2+, UO2

n = 3 for M = Cr(III) and n = 2 for M = Cu(II), Co(II), Mn(II), Ni(II)

CH3 CH2 OH

refluxed 3h

2+, ZrO2+

MCl2

filtered, washed with ether, methanol or ethanol, and dried in vacuo (Figures 1–4).

M2+

,

#### 2.1.2. Synthesis of the complexes with ligands HL6–<sup>11</sup> and various co-ligands

The metal complexes with ligands base Schiff HL6–<sup>11</sup> are obtained through three methods:

Method 1. Previously, the complex combination with the Schiff base is obtained to which the coligand is added(α-picoline, β-picoline, γ-picoline, n-propylamine). After the complete precipitation, the solid compound is obtained that is filtered, washed with ether, and dried in the exicator (Figure 5) [48].

Method 2. The mixture of reaction which contains the alcoholic ligand solutions (the Schiff base and the co-ligand) and the alcoholic solution of metal salt is refluxed for 6–8h. After the concentration of the solution to a third of its volume, on the water bath, a precipitate is obtained which is filtered, washed with alcohol, and dried in vacuo (Figure 6) [49]; (Figure 7) [50, 51].

Figure 5. Scheme of synthesis of complexes with ligand HL6 .

Figure 6. Scheme of synthesis of complexes with ligands HL7–<sup>9</sup> .

Method 3. By adding an ethanolic solution of Schiff base to a metal salt solution, in a molar ratio 1:1, a mixture is obtained which is refluxed for 3–8h. An ethanol solution of co-ligand (amino acids; 1,10-phenanthroline; 2,2<sup>0</sup> - bipyridine; etc.) is added in the reaction environment, and the reflux is kept going on for another 1–3h. The precipitate is obtained which is filtered, washed in ether, and dried in vacuo (Figure 7) [52, 53]; (Figure 8) [54].

### 2.1.3. Synthesis of the complexes with ligands HL10, 12–<sup>14</sup> and various aromatic amine

The metal complexes with these Schiff bases are obtained through refluxing, lasting for 3–4h of a mixture that contains the metal salt dissolved in ethanol and the ligand dissolved in the same solvent. The ligand can be previously obtained through two different methods (Figure 9) [55], respectively (Figure 10) [53, 56–58].

#### 2.1.4. Synthesis of the complexes with ligands HL15 and HL<sup>16</sup>

The metal complexes with ligands Schiff bases HL15 and HL16 are obtained by treating a ligand solution with a solution of metal salt, in a molar ratio L:M=1:1. The mixture is refluxed for 5–6h. After the concentration of the solution to a third of its volume, on the water bath, a precipitate is obtained which is filtered, washed with ether, and dried in vacuo (Figure 11) [59, 60].

### 2.1.5. Synthesis of the complexes with ligands HL17–<sup>20</sup>

The metal complexes with Schiff base ligands HL17–<sup>20</sup> are obtained through treating a solution that contains the ligand dissolved in ethanol or acetonitrile with the solution of metal salt, in a molar ratio of L:M=1:1. The mixture is refluxed for 5–6h (Figures 12, 13) [61–64] or, in other cases, even 12h (Figure 14) [45]. The precipitation begins immediately or after the concentration of the solution to a third of its volume, on a water bath. The precipitate is obtained which is filtered, washed with ether, and dried in vacuo.

Transition Metal Complexes with Antipyrine‐Derived Schiff Bases: Synthesis and Antibacterial Activity http://dx.doi.org/10.5772/67584 71

Figure 7. Scheme of synthesis of complexes with ligand HL10.

Method 3. By adding an ethanolic solution of Schiff base to a metal salt solution, in a molar ratio 1:1, a mixture is obtained which is refluxed for 3–8h. An ethanol solution of co-ligand (amino

.

R = , ,

refluxed 2h

SO4

stirred

reflux is kept going on for another 1–3h. The precipitate is obtained which is filtered, washed

The metal complexes with these Schiff bases are obtained through refluxing, lasting for 3–4h of a mixture that contains the metal salt dissolved in ethanol and the ligand dissolved in the same solvent. The ligand can be previously obtained through two different methods (Figure 9) [55],

The metal complexes with ligands Schiff bases HL15 and HL16 are obtained by treating a ligand solution with a solution of metal salt, in a molar ratio L:M=1:1. The mixture is refluxed for 5–6h. After the concentration of the solution to a third of its volume, on the water bath, a precipitate is

The metal complexes with Schiff base ligands HL17–<sup>20</sup> are obtained through treating a solution that contains the ligand dissolved in ethanol or acetonitrile with the solution of metal salt, in a molar ratio of L:M=1:1. The mixture is refluxed for 5–6h (Figures 12, 13) [61–64] or, in other cases, even 12h (Figure 14) [45]. The precipitation begins immediately or after the concentration of the solution to a third of its volume, on a water bath. The precipitate is obtained which is

obtained which is filtered, washed with ether, and dried in vacuo (Figure 11) [59, 60].

2.1.3. Synthesis of the complexes with ligands HL10, 12–<sup>14</sup> and various aromatic amine

in ether, and dried in vacuo (Figure 7) [52, 53]; (Figure 8) [54].

<sup>+</sup> VOSO4 <sup>+</sup>

Figure 6. Scheme of synthesis of complexes with ligands HL7–<sup>9</sup>

+

70 Descriptive Inorganic Chemistry Researches of Metal Compounds

2.1.4. Synthesis of the complexes with ligands HL15 and HL<sup>16</sup>

2.1.5. Synthesis of the complexes with ligands HL17–<sup>20</sup>

filtered, washed with ether, and dried in vacuo.


acids; 1,10-phenanthroline; 2,2<sup>0</sup>

respectively (Figure 10) [53, 56–58].

Figure 8. Scheme of synthesis of complexes with ligand HL11.

The study methods used to describe the complexes were as follows: the basic chemical analysis, spectrometry IR, UV-VIS, EPR, the thermogravimetric analysis, the magnetic susceptibility, and the molar electric conductibility. The complexes synthetized were tested from the point of view of the antibacterian activity; the obtained results were presented in the respective papers.

#### 2.2. New compounds: structure and antibacterial activity

#### 2.2.1. Structure and synthesis of the compounds 1–28

With a view to obtaining new compounds with significant antibacterian activity, we have synthesized and characterized a series of complexes of Cu(II), Ni(II), Mn(II), and V(IV) with ligands Schiff bases, derived from 4-aminoantipyrine.

In this regard, we have synthesized four ligands, with chromophore groups ONO, respectively, ON, and different volumes of the aldehyde which is a part of Schiff base: 1-phenyl-2,3-dimethyl-4-(N-3-formyl-6-methyl-chromone)-3-pyrazolin-5-one (HL21); 1-phenyl-2,3-dimethyl-4-(N-2 hydroxy-4-methoxy-benzaldehyde)-3-pyrazolin-5-one (HL22); 1-phenyl-2,3-dimethyl-4-(1Hindole-3-carboxaldehyde)-3-pyrazolin-5-one (HL23); 1-phenyl-2,3-dimethyl-4-(N-pyridoxal hydrochloride)-3-pyrazolin-5-one (HL24) as well as their complex combinations with transitional metals: Cu2+, Ni2+, Mn2+, VO2+ (28 metal complexes).

Transition Metal Complexes with Antipyrine‐Derived Schiff Bases: Synthesis and Antibacterial Activity http://dx.doi.org/10.5772/67584 73

Figure 9. Scheme of synthesis of complexes with ligand HL12.

The study methods used to describe the complexes were as follows: the basic chemical analysis, spectrometry IR, UV-VIS, EPR, the thermogravimetric analysis, the magnetic susceptibility, and the molar electric conductibility. The complexes synthetized were tested from the point of view of the antibacterian activity; the obtained results were presented in the respective papers.

AcO AcO

NO2

NO2

/

COO)2 / Co(CH3COO)2

Cu(CH3

With a view to obtaining new compounds with significant antibacterian activity, we have synthesized and characterized a series of complexes of Cu(II), Ni(II), Mn(II), and V(IV) with

In this regard, we have synthesized four ligands, with chromophore groups ONO, respectively, ON, and different volumes of the aldehyde which is a part of Schiff base: 1-phenyl-2,3-dimethyl-4-(N-3-formyl-6-methyl-chromone)-3-pyrazolin-5-one (HL21); 1-phenyl-2,3-dimethyl-4-(N-2 hydroxy-4-methoxy-benzaldehyde)-3-pyrazolin-5-one (HL22); 1-phenyl-2,3-dimethyl-4-(1Hindole-3-carboxaldehyde)-3-pyrazolin-5-one (HL23); 1-phenyl-2,3-dimethyl-4-(N-pyridoxal hydrochloride)-3-pyrazolin-5-one (HL24) as well as their complex combinations with transitional

2.2. New compounds: structure and antibacterial activity

OAc or

NO2

NO2

refluxed 3h

CH3 OH

refluxed 2-3h

CH3 OH

2.2.1. Structure and synthesis of the compounds 1–28

Figure 8. Scheme of synthesis of complexes with ligand HL11.

OAc

OHC

72 Descriptive Inorganic Chemistry Researches of Metal Compounds

NO2

NO2

ligands Schiff bases, derived from 4-aminoantipyrine.

metals: Cu2+, Ni2+, Mn2+, VO2+ (28 metal complexes).

Figure 10. Scheme of synthesis of complexes with ligand HL10.

Figure 11. Scheme of synthesis of complexes with ligands HL15 and HL16.

The study methods used to characterize the metal complexes were as follows: elemental analysis, the thermogravimetric analysis, IR, UV-Vis, EPR spectroscopy, the molar electric conductibility, the magnetic susceptibility, and the X-ray diffraction.

#### 2.2.1.1. Synthesis of the complexes with ligand HL<sup>21</sup>
