**1. Introduction**

Nowadays, one of the greatest imperatives is the synthesis and characterization of new drugs with enhanced activity and safer application [1]. One of the promising groups of compounds in this field is undoubtedly Schiff bases and their metal complexes, due to the ease of synthesis, interesting coordination properties, and wide range of possible applications [2–4]. Research has shown that aromatic carbonyl compounds form stable Schiff bases, while those with aliphatic compounds are prone to polymerization. Also, aromatic derivatives of some therapeutic agents were shown to be safer to use [5].

Having in mind the bond between biological activity and complexation ability [2], thorough examinations have been done to explore the possibilities of syntheses of metal complexes with aromatic Schiff bases, as well as the properties of the obtained compounds. The overview, synthesis, and comparison of some structural features of all so far known metal complexes with selected Schiff bases of some dihydroxybenzaldehydes, 2-acetylpyridine, and 2,6-diacetylpyridine are presented.

## **2. Schiff bases of dihydroxybenzaldehydes**

In this part, the significance, structure, and potential application of the Schiff bases of 2,3-; 2,4-; and 2,5-dihydroxybenzaldehyde (**Figure 1**) and their metal complexes will be presented.

Since the knowledge about the structure of compounds leads to better insight into the mechanism of their activities, thus the prediction of improvements, the search of Cambridge Structural Database (CSD) [6] about the number and structural features of these Schiff bases and their metal complexes has been made. The comparative analysis of structural properties of free Schiff bases and coordinated ones is very important for their future applications.

Imine derivatives of 2,3-; 2,4-; and 2,5-dihydroxybenyzaldehyde are part of the larger group of *o*-hydroxy Schiff bases. These compounds are interesting from the structural point of view, due to their ability to form intramolecular H-bonds. Also, metal complexes with Schiff bases containing phenol group through which the coordination is realized are considered models for important biological reactions, which mimic catalytic behavior of metalloenzymes [7]. Macrocyclic derivatives of these Schiff bases are the basis for the investigation of many biological processes, such as photosynthesis and oxygen metabolism [8].

However, their existence in two different tautomeric forms, that is*,* phenol-imines and keto-amines (**Figure 2**), is one of the crucial factors in the determination of their photochromic and thermochromic properties [9]. Based on the tautomeric form, two types of intramolecular H-bonds could be formed: O∙H∙∙∙N in phenol-imines and N∙H∙∙∙O in keto-amines [9–11]. Another form of Schiff bases is zwitterionic tautomer, which is rather rare compared with the previously described [12]. This is in accordance with our findings based on the search of CSD.

Another interesting feature of dihydroxybenzaldehydes is the presence of another OH-group, which enables the formation of more H-bonds, but also the additional coordination *via* another oxygen atom (*vide infra*).

The CSD search has shown that 75 mono-condensed, 18 bi-condensed, two tricondensed, and two tetra-condensed Shiff bases of 2,3-dihydroxybenzaldehyde have been structurally characterized. The number of structures of the Schiff bases with 2,4-dihydroxybenzaldehyde is similar (79 mono-condensed and 8 bi-condensed), while the number of imine derivatives of 2,5-dihydroxybenzaldehyde is significantly lower—27 structures of mono-condensed and only one structure of bi-condensed Schiff bases. In all of those structures, dihydroxybenzaldehyde fragment is present in its neutral form. As it is said before, the zwitterionic form is rare—29 structures of Schiff bases of 2,3-DHBA, but only 9 and 4 structures of Schiff bases of 2,4- and 2,5-DHBA, respectively. However, there is a certain number of structures in which

**Figure 1.** *Structural formulas of 2,3- (a), 2,4- (b), and 2,5-DHBA (c).*

*Some Aromatic Schiff Bases and Their Metal Complexes DOI: http://dx.doi.org/10.5772/intechopen.107405*

**Figure 2.** *Tautomerism in o-hydroxy Schiff bases.*

two dihydroxybenzaldehyde moieties are present, that isthat is, one in neutral form and the other one in its monodeprotonated form. In the latter, the migration of H-atom from hydroxy-group in position 2 to azomethine nitrogen atom takes place and results in the formation of zwitterion of the Schiff base. This leads to changes in bond lengths, that is, the shortening of the C∙O bond for ca. 0.06–0.07 Å, and the elongation of the C∙N bond for ca. 0.02 Å.

One of the main areas of possible applications of Schiff bases, in general, is medicine or pharmacology. From this point of view, the most important characteristic of Schiff bases and an essential structural requirement for biological activity is their ability to cleave DNA [13]. The condensation of 2,3-, and 2,4-DHBA with tert-butylamine described in [14] gave two types of compounds. The analysis of the binding of these two ligands to human serum albumin (HSA) indicates the dominance of the latter. H-bonds stabilize the albumin-ligand system and have the main role in this type of binding.

Almost half a century ago, attempts for finding a cure for sickle cell anemia included the investigation of Schiff bases formed by amino groups of intracellular hemoglobin with aromatic aldehydes, such as 2,3-DHBA. Hydroxyl group as a substituent can lead 2,3-DHBA to specific hemoglobin sites, important for oxy-deoxy equilibrium. In this way, the affinity of sickle cells toward oxygen is increased, thus can lead to the mitigation of the effects of this disease [15].

The search of CSD revealed 136 structures of complex compounds with Schiff bases of 2,3-DHBA with 3d-, 4d-, 4f-, and s-metals, as well as uranium and organotin compounds. In the largest number of these complexes, Schiff bases have the role of tridentate (33 structures) (**Figure 3a**) and tetradentate ligand (**Figure 4a** and **b**) (20 structures). Significantly less common are bidentate (9 structures), pentadentate (2 structures), and hexadentate (2 structures) coordination of a chelating ligand. Due to the existence of two neighboring hydroxy groups, the coordination modes of these ligands could be described as versatile. In ca. 50 structures, additional bridging coordination of oxygen atom of one or both hydroxy groups is found (**Figure 3e**). Structures of numerous mixed complexes with these ligands containing 4f-metal centers are determined. A series of four mixed complexes with palladium and 4f-metals stands out. In these complexes besides the tetradentate ONNO coordination of the Schiff base, four oxygen donors of the neighboring OH-groups are coordinated to another metal center (**Figure 4d**). Also, one organometallic compound of palladium(II) is structurally characterized [16].

Complexes of 2,4-DHBA Schiff bases containing 3d-, 4d-metals, organotin compounds, lead and uranium are structurally characterized. The most common

**Figure 3.**

*The most common modes of tridentate (a) and additional bridging coordination (b-e) of Schiff bases of 2,3- DHBA (R1 = OH, R2 = R3 = H), 2,4-DHBA (R2 = OH, R1 = R3 = H), and 2,5-DHBA (R3 = OH, R1 = R2 = H).*

coordination modes are ONX (X = O, N, S) tridentate (43 structures) (**Figure 3a**) and ONNO, ONNN, and ONOO tetradentate (42 structures). Unlike those, there are only 11 and 14 structures with bidentate and hexadentate coordination of these ligands, respectively. In a certain number of structures, bridging coordination of these Schiff bases is found, that is, in 8 structures besides the three donor atoms, an additional coordination bond is realized through some atom of the imine residue (**Figure 3c** and **d**), while in the other 8 structures, the bridging atom is deprotonated phenolic oxygen from the position 2 (**Figure 3b**). In the other 8 structures, both of those bridging coordination modes are proven. Finally, there are 5 structures with tetradentate and additional bridging coordination of another donor atom, as well as two structures with bidentate coordinated Schiff base and bridging of an oxygen atom from position 2 of the 2,4-DHBA moiety.

On the contrary, there are far fewer structures of the complexes with Schiff basses of 2,5-DHBA—only 12 complexes with 3d-metals and organotin. Nevertheless, the coordination modes of these ligands are numerous—in two structures bidentate coordination mode is found, in three structures—tridentate, in four structures tetradentate, and in three structures additional bridging coordination of phenolic oxygen atom and/or another donor atom of imine residue (**Figure 3c–e**).

Unlike OH-group from position 3 in 2,3-DHBA residue, in Schiff bases of 2,4- DHBA and 2,5-DHBA additional hydroxy groups (from positions 4 and 5, respectively) do not take part in coordination.

In the silver(I) complex (Ref. code MICVUS) [17] the organic ligand is coordinated in an exotridentate manner to three metal ions (**Figure 5**). It is interesting to note that the protonated hydroxy group of 2,4-DHBA residue is involved in coordination.

*Some Aromatic Schiff Bases and Their Metal Complexes DOI: http://dx.doi.org/10.5772/intechopen.107405*

**Figure 4.**

*The most common modes of tetradentate (a-c) and additional bridging coordination (d) of Schiff bases of 2,3- DHBA (R1 = OH, R2 = R3 = H), 2,4-DHBA (R2 = OH, R1 = R3 = H), and 2,5-DHBA (R3 = OH, R1 = R2 = H).*

**Figure 5.** *Molecular structure of Ag(I) complex with the Schiff base of 2,4-DHBA.*

Dihydroxybenzaldehyde residue does not take part in coordination in two ferrocene derivatives (Ref. codes OWUXUB [18] and RUTYIP [19]), as well as in three Cu(I) complexes (Ref. codes VAHHUL, VAHJIB, and VAHKIC) [20] and one silicone complex (Ref. code XOSMOJ) in which the coordination is realized through the residue of the imine ligand precursor [21].

Besides, in one cadmium(II) complex (Ref. code QEWFUW) [22], the Schiff base of 2,4-DHBA is present in its neutral form but is not involved in coordination. Also, in two complexes of potassium and calcium (Ref. codes MAVNEE and MAVNII) [23] coordination is accomplished *via* sulfonato oxygen atoms, without the involvement of a 2,4-DHBA fragment. This is a good example of Pearson's theory of hard and soft acids and bases.

Schiff bases of 2,3-DHBA and their metal complexes showed to be important in the area of supramolecular chemistry, as precursors for obtaining octanuclear cluster compounds of zinc(II) [24], and some of them show significant photoluminescence [25]. Bidentate Schiff base of 2,3-DHBA and alkylamines is reported to be a good chelating ligand with significant selectivity and sensitivity for Co(II), Cu(II), and Fe(II) ions [26]. The asymmetric Schiff base obtained by condensation of allylamine has good antimicrobe activity, even better than its complex with Mo(VI) [27].

Octahedral complexes of chromium(III) with Schiff bases of metformin and 2,3- DHBA, 2,4-DHBA, 2,5-DHBA, and 3,4-DHBA are obtained by template reactions. For the complex with 2,4-DHBA Schiff base, [CrLCl(H2O)2]∙3H2O, the research revealed the potential effect in lowering blood glucose levels [28].

A structurally interesting compound is the complex of zinc(II) with the Schiff base of 2,3-DHBA and aminoguanidine, of the formula [Zn2L(CH3COO)2]2∙2MeCN (**Figure 6**). The asymmetric unit consists of the dianion of the chelating ligand, which is in an ONN tridentate manner coordinated to one metal center, and in a monodentate manner (*via* the oxygen atom of the deprotonated hydroxy group from position 3) to another zinc(II) ion, two acetate ions that have a bridging role, and one solvent molecule [29].

The research has shown that the tridentate Schiff base of 2,4-DHBA and aminoguanidine expresses antioxidative and antiglycation effects, similar to the Schiff base of pyridoxal and aminoguanidine. However, the Schiff base with 2,4-DHBA had a better *in vivo* antithrombic effect and thus could be useful in the treatment of diabetic complications [30]. One square-planar complex of copper(II) with this Schiff base has been synthesized and structurally characterized (**Figure 7**). In this complex, the chelating ligand is coordinated through the oxygen atom of the deprotonated hydroxy

*Some Aromatic Schiff Bases and Their Metal Complexes DOI: http://dx.doi.org/10.5772/intechopen.107405*

**Figure 6.**

*Molecular structure of [Zn2L(CH3COO)2]2∙2MeCN.*

**Figure 7.** *Molecular structure of the complex [Cu(L-H)Cl]·nH2O (n = 4) (water molecules are not shown).*

group from position 2, the nitrogen atom of the azomethine group, and the nitrogen atom of the imine group of the aminoguanidine fragment [31].
