A Palladium Catalyst System for the Efficient Cross-Coupling Reaction of Aryl Bromides and Chlorides with Phenylboronic Acid: Synthesis and Biological Activity Evaluation

New benzimidazolium salts 1a–c and their palladium bis-N-heterocyclic carbene complexes 2a–c and palladium PEPPSI-type complexes 3a–c were designed, synthesized and structurally characterized by NMR (1H and 13C), IR, DART-TOF mass spectrometry and elemental analysis. Then these complexes 2–3 were employed in the Suzuki-Miyaura cross-coupling reaction of substituted arenes with phenylboronic acid under mild conditions in toluene and DMF/H2O (1/1) to afford functionalized biaryl derivatives in good to excellent yields. The antibacterial activity of palladium bis-N-heterocyclic carbene complexes 2a–c and palladium PEPPSI-type complexes 3a–c was measured by disc diffusion method against Gram positive and Gram negative bacteria. Compounds 2a, 2c and 3a–c exhibited potential antibacterial activity against four bacterial species among the five used indicator cells. The product 2b inhibits the growth of the all five tested microorganisms. Moreover, the antioxidant activity determination of these complexes 2–3, using 2.2-diphenyl-1-picrylhydrazyl (DPPH) as a reagent, showed that compounds 2a–c and 3b possess DPPH antiradical activity. The higher antioxidant activity was obtained from the product 2b which has radical scavenging activity comparable to that of the two used positive controls (gallic acid “GA“ and tutylatedhydroxytoluene “BHT“). Investigation of the anti-acetylcholinesterase activity of the studied complexes showed that compounds 2b, 3a, and 3b exhibited moderate activity at 100 μg/mL and product 2b is the most active.


Introduction
N-heterocyclic carbene (NHC) ligands have become ubiquitous in the preparation of metal complexes with new catalytic applications. Mainly due to their applications in C-C bond formation review articles describing their chemistry have been published. In an attempt to provide a new vision of the topic, this article will focus our attention on the development of new palladium complexes with NHC ligands, paying special attention to their applications in catalytic processes other than the classical C-C coupling [1][2][3][4].
A wide range of NHC ligands which exhibit high activities in various important organic transformations when combined with metal pre-catalysts are now commercially available [5][6][7]. NHC imidazolidine ligands with sterically encumbering groups such as mesityl, 2,6-diisopropylphenyl, and adamantyl have been used in the Pd-catalyzed cyclization of anilides [8],amination of aryl chlorides [9], arylation with ester enolates to afford α-aryl esters [10]. Sonogashira reactions of unactivated alkyl bromides [11] and the ruthenium-catalyzed RCM reaction [12]. The coupling of aryl halides with organoboronic acids is one of the most important palladium-catalyzed cross-coupling reactions of both academic and industrial interest. In particular for the preparation of biaryl-containing molecules [13,14].
The reaction is the organic reaction of an aryl-or vinylboronic acid with an aryl or vinylhalide catalyzed by a palladium (0) complex. It is widely used to synthesize polyolefins, styrenes, and substituted biphenyls, and has been extended to incorporate alkyl bromides. Several reviews have been published [15][16][17]. However, the development of new ligands or the application of existing ligands in Suzuki reaction, particularly involving aryl chlorides as substrates, is still of considerable importance. In order to find more efficient palladium catalysts we have prepared a series of new (NHCs) stable NHC-PdCl2 pyridine complexes for the Suzuki coupling reaction.
Therefore, in this work, we describe the synthesis and characterization of new palladium (II) complexes. We also examined catalytic activities of these Pd (II) complexes 2-3 in the Suzuki-Miyaura cross-coupling reaction. The antibacterial, antioxidant and anti-acetylcholinesterase activities of the new synthesized complexes 2-3 were addressed as well.

Preparation of Benzimidazolium Salts 1a-c
The precursors 1a-c were prepared by the quaternization of the intermediate A with a variety of aryl chlorides or aryl bromides in DMF under 70 °C (Scheme 1). The benzimidazolium salts 1a-c were obtained as white solids in very high to good yields of 95%, 90% and 79%, respectively. The imino carbons (NCHN) were detected as typical singlets in the 1 H decoupled mode at 141.7, 143.0, and 143.39 ppm. The IR data of 1a, 1b and 1c clearly support the presence of the C-N group with ν(C-N) vibrations at 1545, 1570 and 1623 cm −1 respectively.

Preparation of bis-NHC-palladium Complexes 2a-c and PEPPSI-type Complexes 3a-c
In order to obtain the PEPPSI-type complexes 3a-c; we employed a reaction between PdCl2 and benzimidazolium salts 1a-c in pyridine at 80 °C in the presence of K2CO3. Further, direct reaction of one equivalents of benzimidazolium salts 1a-c with PdCl2 stirred at reflux in THF for 24 h in the presence of K2CO3 results in palladium complex formation 2a-c ( Figure 2). Structural definitions of 2a-c and 3a-c were determined by NMR, IR spectroscopy, DART-TOF mass spectrometry and elemental analysis. The 1 H-NMR spectra of compounds 2a-c and 3a-c were taken in CDCl3 at room temperature. In the 1 H-NMR spectrum of 2a, the aromatic protons appeared at between 6.28 and 7.24 ppm as a multiplet while methylic protons appeared between 1.98 and 2.42 ppm as singlets. In the 1 H-NMR spectra of 3a-c, (NCH2) was resonated at low fields δ 6. 27, 6.24  The imino carbons (NCHN) were detected as typical singlets in the 1 H decoupled mode at 141.7, 143.0, and 143.39 ppm. The IR data of 1a, 1b and 1c clearly support the presence of the C-N group with ν(C-N) vibrations at 1545, 1570 and 1623 cm −1 respectively.

Preparation of bis-NHC-palladium Complexes 2a-c and PEPPSI-type Complexes 3a-c
In order to obtain the PEPPSI-type complexes 3a-c; we employed a reaction between PdCl 2 and benzimidazolium salts 1a-c in pyridine at 80 • C in the presence of K 2 CO 3 . Further, direct reaction of one equivalents of benzimidazolium salts 1a-c with PdCl 2 stirred at reflux in THF for 24 h in the presence of K 2 CO 3 results in palladium complex formation 2a-c ( Figure 2). The imino carbons (NCHN) were detected as typical singlets in the 1 H decoupled mode at 141.7, 143.0, and 143.39 ppm. The IR data of 1a, 1b and 1c clearly support the presence of the C-N group with ν(C-N) vibrations at 1545, 1570 and 1623 cm −1 respectively.

Preparation of bis-NHC-palladium Complexes 2a-c and PEPPSI-type Complexes 3a-c
In order to obtain the PEPPSI-type complexes 3a-c; we employed a reaction between PdCl2 and benzimidazolium salts 1a-c in pyridine at 80 °C in the presence of K2CO3. Further, direct reaction of one equivalents of benzimidazolium salts 1a-c with PdCl2 stirred at reflux in THF for 24 h in the presence of K2CO3 results in palladium complex formation 2a-c ( Figure 2). Structural definitions of 2a-c and 3a-c were determined by NMR, IR spectroscopy, DART-TOF mass spectrometry and elemental analysis. The 1 H-NMR spectra of compounds 2a-c and 3a-c were taken in CDCl3 at room temperature. In the 1 H-NMR spectrum of 2a, the aromatic protons appeared at between 6.28 and 7.24 ppm as a multiplet while methylic protons appeared between 1.98 and 2.42 ppm as singlets. In the 1 H-NMR spectra of 3a-c, (NCH2) was resonated at low fields δ 6.27, 6.24  Structural definitions of 2a-c and 3a-c were determined by NMR, IR spectroscopy, DART-TOF mass spectrometry and elemental analysis. The 1 H-NMR spectra of compounds 2a-c and 3a-c were taken in CDCl 3 at room temperature. In the 1 H-NMR spectrum of 2a, the aromatic protons appeared at between 6.28 and 7.24 ppm as a multiplet while methylic protons appeared between 1.98 and 2.42 ppm as singlets. In the 1 H-NMR spectra of 3a-c, (NCH 2 ) was resonated at low fields δ 6.27, 6.24 and 6.08 respectively. While signals for the pyridine ring protons appeared between 7.36-8.94 ppm, 7.33-8.94 ppm and 7.28-8.91 ppm, respectively ( Figure 3).  The absence of NCHN signal proton in a downfield for 2-3 indicated the successful formation of NHC complexes. The 13 C-NMR spectra of complexes 2a-c and 3a-c were in good correlation with the structure of these compounds. 13 C{ 1 H} NMR spectra prove an increasing downfield shift of the NCN carbon from 1a-c to 2a-c: for example, the 13 C{ 1 H}N-C-N shifts of 1a and 2a, which are 141.7 and 180.8 ppm, respectively. The NCHN carbons for 3a-c resonated at δ 161.9, 163.3 and 162.8 ppm respectively ( Figure 4).  The absence of NCHN signal proton in a downfield for 2-3 indicated the successful formation of NHC complexes. The 13 C-NMR spectra of complexes 2a-c and 3a-c were in good correlation with the structure of these compounds. 13 C{ 1 H} NMR spectra prove an increasing downfield shift of the NCN carbon from 1a-c to 2a-c: for example, the 13 C{ 1 H}N-C-N shifts of 1a and 2a, which are 141.7 and 180.8 ppm, respectively. The NCHN carbons for 3a-c resonated at δ 161.9, 163.3 and 162.8 ppm respectively ( Figure 4).  The absence of NCHN signal proton in a downfield for 2-3 indicated the successful formation of NHC complexes. The 13 C-NMR spectra of complexes 2a-c and 3a-c were in good correlation with the structure of these compounds. 13 C{ 1 H} NMR spectra prove an increasing downfield shift of the NCN carbon from 1a-c to 2a-c: for example, the 13 C{ 1 H}N-C-N shifts of 1a and 2a, which are 141.7 and 180.8 ppm, respectively. The NCHN carbons for 3a-c resonated at δ 161.9, 163.3 and 162.8 ppm respectively ( Figure 4).   The functional groups of complexes 2-3 were identified by FT-IR spectroscopy. The IR(CN) band was observed at 1445 cm −1 for 2a, 1462 cm −1 for 2b and1463 cm −1 for 2c in the FT-IR spectra. The same band shifted and appeared at 1461, 1463 and 1460 cm −1 for 3a-c, respectively.
The contents of C, H, and N in palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c were determined by elemental analysis. The results agreed well with the theoretical formula of the complex.
The obtained fragments are typical for each palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c and can provide further evidence for the characterization of the examined compounds. The MS spectrum of complex 3a is given in Figure 5. The functional groups of complexes 2-3 were identified by FT-IR spectroscopy. The IR(CN) band was observed at 1445 cm −1 for 2a, 1462 cm −1 for 2b and1463 cm −1 for 2c in the FT-IR spectra. The same band shifted and appeared at 1461, 1463 and 1460 cm −1 for 3a-c, respectively.
The contents of C, H, and N in palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c were determined by elemental analysis. The results agreed well with the theoretical formula of the complex.
The obtained fragments are typical for each palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c and can provide further evidence for the characterization of the examined compounds. The MS spectrum of complex 3a is given in Figure 5. The fragmentation leading to the m/z = 263 can occur via the mechanism of fragmentation given in Figure 6. In order to demonstrate the utility of these NHC-PdCl2-pyridine complexes, we used them as co-catalysts in Suzuki-Miyaura cross-coupling reaction, which are common industry-applicable processes.

Suzuki Coupling Reaction of Aryl Chlorides/Bromides with Phenylboronic Acid
In a pilot study to examine the catalytic activity of bis NHC-palladium complexes 2a-c and PEPPSI-type complexes 3a-c, we initially tested the Suzuki cross coupling reaction between 4-chloroacetophenone and phenylboronic acid as a model reaction to determine optimum conditions. Here we compared both the effect of using toluene or DMF/H2O as the solvent, as well us using KOtBu or K2CO3 as the mineral base. As can be seen in Table 1, the best catalytic activities were only The fragmentation leading to the m/z = 263 can occur via the mechanism of fragmentation given in Figure 6. The functional groups of complexes 2-3 were identified by FT-IR spectroscopy. The IR(CN) band was observed at 1445 cm −1 for 2a, 1462 cm −1 for 2b and1463 cm −1 for 2c in the FT-IR spectra. The same band shifted and appeared at 1461, 1463 and 1460 cm −1 for 3a-c, respectively.
The contents of C, H, and N in palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c were determined by elemental analysis. The results agreed well with the theoretical formula of the complex.
The obtained fragments are typical for each palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c and can provide further evidence for the characterization of the examined compounds. The MS spectrum of complex 3a is given in Figure 5. The fragmentation leading to the m/z = 263 can occur via the mechanism of fragmentation given in Figure 6. In order to demonstrate the utility of these NHC-PdCl2-pyridine complexes, we used them as co-catalysts in Suzuki-Miyaura cross-coupling reaction, which are common industry-applicable processes.

Suzuki Coupling Reaction of Aryl Chlorides/Bromides with Phenylboronic Acid
In a pilot study to examine the catalytic activity of bis NHC-palladium complexes 2a-c and PEPPSI-type complexes 3a-c, we initially tested the Suzuki cross coupling reaction between 4-chloroacetophenone and phenylboronic acid as a model reaction to determine optimum conditions. Here we compared both the effect of using toluene or DMF/H2O as the solvent, as well us using KOtBu or K2CO3 as the mineral base. As can be seen in Table 1, the best catalytic activities were only In order to demonstrate the utility of these NHC-PdCl 2 -pyridine complexes, we used them as co-catalysts in Suzuki-Miyaura cross-coupling reaction, which are common industry-applicable processes.

Suzuki Coupling Reaction of Aryl Chlorides/Bromides with Phenylboronic Acid
In a pilot study to examine the catalytic activity of bis NHC-palladium complexes 2a-c and PEPPSI-type complexes 3a-c, we initially tested the Suzuki cross coupling reaction between 4-chloroacetophenone and phenylboronic acid as a model reaction to determine optimum conditions. Here we compared both the effect of using toluene or DMF/H 2 O as the solvent, as well us using KOtBu or K 2 CO 3 as the mineral base. As can be seen in Table 1, the best catalytic activities were only We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K 2 CO 3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2.   With the best conditions in hand, next we conducted further experiments to investigate the scope of the Suzuki cross-coupling reaction of catalysts 2 with various substrates, including aryl bromides and chlorides having electro N-withdrawing or electro N-donating substituents (  With the best conditions in hand, next we conducted further experiments to investigate the scope of the Suzuki cross-coupling reaction of catalysts 2 with various substrates, including aryl bromides and chlorides having electro N-withdrawing or electro N-donating substituents (   With the best conditions in hand, next we conducted further experiments to investigate the scope of the Suzuki cross-coupling reaction of catalysts 2 with various substrates, including aryl bromides and chlorides having electro N-withdrawing or electro N-donating substituents ( We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. We tested the effect of common mineral bases such as K2CO3 and KO t Bu for the Suzuki coupling reactions of aryl chlorides. 1 (eq) of KO t Bu showed high performance in these catalytic systems. On the other hand, one can easily observe in Table 2 that a typical reaction of 4-chloroacetophenone and phenylboronic acid indicated that the reaction rate depended on the alkyl substituents. It can also be seen from Table 3 that the efficiency of complexes is not the same for each complex. For instance, the Suzuki cross-coupling reaction with catalyst 3always afforded higher catalytic activity than that with catalyst 2. Conversions were determined by GC. Conversions were determined by GC. With the best conditions in hand, next we conducted further experiments to investigate the scope of the Suzuki cross-coupling reaction of catalysts 2 with various substrates, including aryl bromides and chlorides having electro N-withdrawing or electro N-donating substituents ( Table 2). The highest conversion was up to 91% in the presence of KO t Bu within 6 h in toluene at 80 • C for catalyst 2b with bromoanisole. On the other hands PEPPSI-type complexes afforded the efficient coupling of different aryl bromides and chloroacetophenone (Table 3), and in most cases the yield was higher than 90%, the reaction showed a good tolerance of different groups on the aromatic ring.
When aryl chlorides were used as substrates, coupling products were formed with a lower yield (Tables 2 and 3) chloroanisole and chlorotoluene (entry [4][5][6][7][8][9]. This was expected on the basis of the higher values of the C-Cl bond energy with respect to C-Br. Nevertheless, good results were obtained for 4-chloroacetophenone.

Antibacterial Activity
The synthesized compounds palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c were evaluated in vitro for their antibacterial activity by the well diffusion method (Table 4).
-Globally, all complexes tested showed an important antibacterial activity against the three used Gram positive bacteria Micrococcus luteus LB 14110, Staphylococcus aureus ATCC 6538 and Listeria monocytogenes ATCC 19117. Concerning the activity against the two tested Gram negative microorganisms, all complexes inhibit the growth of Salmonella Typhimurium ATCC 14028 except the product 3c and only the compound 2b presents an inhibitory effect against Pseudomonas aeruginosa ATCC 49189 (Table 4). In

DPPH Radical Scavenging
The hydroxyl radical is one of the most reactive products of reactive oxygen species (ROS). Among all free radicals, the hydroxyl radical is by far the most potent and therefore the most dangerous oxygen metabolite, which would result in cell membrane disintegration, membrane protein damage, DNA mutation and further initiate or propagate the development of many diseases. Elimination of this radical is one of the major aims of antioxidant administration [18]. Current research has shown that some antioxidants could act as the inducers of DNA damage response, which leads to cell death [19]. Therefore, in present study, we investigated whether the palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c could serve as a potent antioxidant. The scavenging activities of the complex on the DPPH radical were investigated. The radical was generated according to the method in the Experimental Section. From the results, we can see that, within the range of tested concentration, the average suppression ratios of DPPH increase along with the increase of the complex concentration (Figure 7). As shown in Figure 7 the compound 2b showed higher antioxidant activity than other complexes. However the scavenging activity of the compound 2b was very similar to that of the two used controlsbutylatedhydroxytoluene (BHT) and gallic acid (GA) known as good antioxidant compounds. No antioxidant activity was observed for the compounds 3a and 3c.

Acetylcholinesterase Inhibition
The acetylcholinesterase enzyme (AChE) is an attractive target for the rational drug design and for the discovery of mechanism based inhibitors because of its role in the hydrolysis of the neurotransmitter acetylcholine (ACh). AChE inhibitors are the most effective approach to treat the cognitive symptoms of Alzheimer disease (AD) [20,21], and other possible therapeutic applications in the treatment of Parkinson′s disease, senile dementia, and ataxia, among others [22].
The results of AChEI of the synthesized compounds palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c are presented in Table 6. Three compounds 2b, 3a, and 3b exhibited moderate AChEI activity at 100 μg/mL. As the antibacterial and antioxidant activities, the compound 2b possesses the most active AChEI activity.

General Information
All manipulations were performed using Standard Schlenck techniques under Argon atmosphere. Chemicals were purchased from Sigma Aldrich and used without further purification. All solvents As shown in Figure 7 the compound 2b showed higher antioxidant activity than other complexes. However the scavenging activity of the compound 2b was very similar to that of the two used controlsbutylatedhydroxytoluene (BHT) and gallic acid (GA) known as good antioxidant compounds. No antioxidant activity was observed for the compounds 3a and 3c.

Acetylcholinesterase Inhibition
The acetylcholinesterase enzyme (AChE) is an attractive target for the rational drug design and for the discovery of mechanism based inhibitors because of its role in the hydrolysis of the neurotransmitter acetylcholine (ACh). AChE inhibitors are the most effective approach to treat the cognitive symptoms of Alzheimer disease (AD) [20,21], and other possible therapeutic applications in the treatment of Parkinson s disease, senile dementia, and ataxia, among others [22].
The results of AChEI of the synthesized compounds palladium bis-N-heterocyclic carbene complexes 2a-c and palladium PEPPSI-type complexes 3a-c are presented in Table 6. Three compounds 2b, 3a, and 3b exhibited moderate AChEI activity at 100 µg/mL. As the antibacterial and antioxidant activities, the compound 2b possesses the most active AChEI activity.

General Information
All manipulations were performed using Standard Schlenck techniques under Argon atmosphere. Chemicals were purchased from Sigma Aldrich and used without further purification. All solvents were purified and dried by MBraun SPS 800 solvent purification system. Column chromatography was performed using silica gel 60 (70-230 mesh). 1 H-NMR and 13 C-NMR spectra were recorded at 300 MHz and 75 MHz, respectively. Chemical shifts, δ, are reported in ppm relative to the internal standard TMS for both 1 H-and 13 C-NMR. The products were characterized by GC (gas chromatography). Quantitative GC analyses were performed with a GC-2010 Plus gas chromatography (SHIMADZU). The NMR studies were carried out in high-quality 5 mm NMR tubes. Signals are quoted in parts per million as δ downfield from tetramethylsilane (δ = 0.00) as an internal standard. NMR multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, m = multiplet signal. IR spectra were recorded on a 398 spectrophotometer (Perkin-Elmer, King Saud University, Ryadh, Saudi Arabia). MS spectra were recorded on a ((DART-TOF-MS) instrument at King Saud University, Ryadh, Saudi Arabia). Elemental microanalysis was performed on an ElementarVario El III Carlo Erba 1108 elemental analyzer (INRAP, Sidi Thabet, Tunisia) and the values found were within ±0.3% of the theoretical values. Melting points were determined with Kofler bench at Isste of Borj Cedria (Hammam Lif, University of Carthage, Borj Cedria, Tunisia).

Synthesis of 1-(3,5-Dimethylbenzyl)-5,6-dimethylbenzimidazole (A)
To a solution of 5, 6-dimethylbenzimidazole (3 mmol, 4.38 g) resolved in 25 mL EtOH, (4 mmol, 2.5 g) of KOH was added and the reaction mixture was stirred for 15 min at room temperature. The corresponding aryl chlorides or bromides (3 mmol) were added slowly and the resulting mixture was stirred at room temperature for 1h and then heated for 8 h at 50 • C, after it was heated under reflux for 16 h. Solution was cooled to room temperature and the solvent was removed under reduced pressure. The yellow solid that formed was resolved with DCM (40 mL) and filtered. DCM was evaporated and the isolated product was characterized by NMR spectroscopy. Yield: 100(%). M.p. = 230 • C. FT-IR (KBr) ν, cm −1 : 3065 (C-Harom); 1406 (C-N). 1

General Preparation of Benzimidazolium Salts 1a-c
To a solution of 5,6-dimethylbenzimidazole (3 mmol, 4.38 g) resolved in EtOH (25 mL) KOH (4 mmol, 2.5 g) was added and the reaction mixture was stirred for 15 min at room temperature. The corresponding aryl chlorides or bromides (3 mmol, 3equiv.) were added slowly and the resulting mixture was stirred at room temperature for 1h and then heated for 8 h at 50 • C, after it was heated under reflux for 16 h. Solution was cooled to room temperature and the solvent was removed under reduced pressure. The yellow solid that formed was resolved with DCM (40 mL) and filtered. DCM was evaporated and the isolated product was characterized by NMR spectroscopy.
A mixture of crude product (1 g) and corresponding aryl chlorides or bromides in DMF (2 mL) was stirred and heated at 70 • C for 1-2 days. The white solid that formed was washed with diethyl ether (30 mL), filtrated and dried under vacuum.

MIC Determination
The antimicrobial activities of the synthesized compounds were determined by the minimum inhibitory concentration (MICs) in accordance with NCCLS guideline M7-A 6 and M38-P [24]. The test was performed in sterile 96-well microplates with a final volume in each microplate well of 100 µL. The synthesized compounds (20 mg/mL) were properly prepared in solution of dimethylsulfoxide (DMSO)/water (1/9; v/v). The inhibitory activity of each synthesized compound was transferred to each well in order to obtain a twofold serial dilution of the original sample and to produce the concentration range of 0.0048-20 mg/mL.

DPPH Radical Scavenging Activity
DPPH possess a proton free radical, when DPPH encounters proton radical scavengers its purple color fades rapidly. This assay determines the scavenging of stable radical species according to the method of [25], with slight modifications. Briefly, synthesized compounds were dissolved in dimethylsulfoxide (DMSO)/water (1/9; v/v) and diluted with ultrapure water at different concentrations (1, 0.5, 0.250, 0.125, 0.0625, 0.03125 mg/mL). Then, 500 µL of a 4% (w/v) solution of DPPH radical in methanol was mixed with 500 µL of samples. The mixture was incubated for 30 min in the dark at room temperature. The scavenging capacity was determined spectrophotometrically by monitoring the decrease in absorbance at 517 nm against a blank. The percentage of antiradical activity (% ArA) had been calculated as follows: % ArA = [(absorbance of control − absorbance of test sample)/absorbance of control] × 100. All tests are assayed in triplicate and expressed as the average ± standard deviation of the measurements.

Acetylcholinesterase Inhibitory Potential
AChE inhibitory activity was measured by slightly modified spectrophotometric method of Ellman et al. [26]. Electric eel AChE was used, while acetylthiocholine iodide (ATCI) was employed as substrate of the reaction. 5.5 -dithiobis-(2-nitrobenzoic acid) (DTNB) was used for the measurement of the antiacetylcholinesterase activity. Briefly, in this method, 100 µL of Tris buffer at 50 mM (pH 8.0), 30 µL of sample or standard and 5 µL of AChE enzyme (0.5 U/mL) were added in a 96 well microplate and incubated for 10 min at 25 • C. Then, 142 µL of DTNB (3 mM) and 23 µL of substrate (75 mM) were added. Percentage of inhibition of AChE was determined by comparison of rates reaction of samples relative to control (10% DMSO in Tris buffer) using the following formula: % AChEI = 1 − (δA sample/δA control) × 100 where δA sample: Sample absorbance at zero time − Sample absorbance at the end of reaction, and δA control: Control absorbance at zero time − Control absorbance at the end of reaction. Galanthamine, an antiacetylcholinesterase alkaloid type of drug obtained from the snowdrop bulbs (Galanthus sp.), was used as standard. All synthesized compounds have been tested at 100 µg/mL of concentration. This determination was done in triplicate and obtained results were very similar. The reported value is the average of the three tests.

Conclusions
In summary, a simple route for the synthesis of palladium (II) complexes containing N donor ligands has been successfully demonstrated and the products fully characterized by NMR, IR, DART-TOF mass spectrometry and elemental analysis. These air and moisture stable palladium (II) complexes efficiently catalyze the cross-coupling of aryl bromides and chlorides (from electron rich to electron poor) with phenylboronic acid in DMF/H 2 O at 80 • C for 24 h, using KO t Bu or K 2 CO 3 as bases, without addition of free ligand or any promoting additive, no significant homocoupling of phenylboronic acid to unsubstituted biphenyl was observed.
The obtained complexes 2a-c and 3a-c were tested for their antibacterial activity against Micrococcus luteus LB 14110, Staphylococcus aureus ATCC 6538, Listeria monocytogenes ATCC 19117, Salmonella Typhimurium ATCC 14028 and Pseudomonas aeruginosa ATCC 49189. Obtained results show that the obtained complexes 2a-c and 3a-c have an effective antibacterial activity against the used indicator bacteria. However, it should be noted that the product 2b strongly inhibits the growth of the all tested food-borne pathogens and clinical microorganisms. Interestingly, this compound 2b, possesses scavenging activity very similar to that of the two well-known antioxidant standards butylatedhydroxytoluene (BHT) and gallic acid (GA). Three compounds 2b, 3a, and 3b exhibited moderate AChEI activity and the product 2b was the most active, with an acetylcholinesterase inhibitory activity of 38.15% at 100 µg/mL. Though the complexes showed slightly more antibacterial activities than other reported complexes, their strong abilities to bind with DNA and scavenge free radicals compared to other reported palladium complexes was notable [27][28][29][30].