Synthesis of Zn compounds derived from 1H -benzimidazol-2-ylmethanamine

The influence of the pH on the synthesis of Zn(II) complexes derived from 1H -benzimidazol-2- ylmethanamine (HL) has been investigated with X-ray crystallography, FAB mass spectrometry, NMR, infrared and Raman spectroscopy. The crystal structures of ( 1H -benzimidazol-2- ylmethanamine)tetrachlorozincate(2) dihydrogen


Introduction
7][8] Normally, the Zn(II) ion has a tetrahedral geometry in the active site, however, the coordination and geometry of this ion depend on the acid-base properties of the histidine residues. 4,6,9The presence of imidazolic-histidine residues, that can donate or accept various protons, allows different types of Zn coordination in the active site.Thus, the activity of the zinc-metalloenzymes has a delicate and sensitive dependence of pH values. 68][9] In our ongoing research on benzimidazole derivatives we are interested in the coordinating acid and behavior of 1H-benzimidazol-2-ylmethanamine (HL) 1. [10][11][12][13] Compound 1 has three pKa values (Scheme 1); at pH below 2.9 the three nitrogen atoms are blocked by protons (H 3 L 2+ ) and apparently this benzimidazole could not coordinate to Zn(II). 11hen the pH values increase 1 could act as a mono-or bidentate ligand.In any of three cases, the coordinated form of the metallic ion will be different.On the other hand, it is known that Zn(II) is selective for coordination of chloride ions because they are small and hydrophilic species. 14,15In the presence of Cl -ions the formation of Zn(II) complexes is favored because of the existence of intermolecular hydrogen bonds. 14In this paper we studied the synthesis of four complexes at different pH, concentration and reaction times in order to analyze the factors that determine the coordination of Zn(II) ions to 1H-benzimidazol-2-ylmethanamine.These compounds were also characterized using NMR, X-ray crystallography, infrared and Raman spectroscopies.

Results and Discussion
In aqueous solution, Zn(II) presents a set of chemical equilibria that basically depend on the ion concentration and pH.The predominance-existence diagrams show that Zn(II) species can only occur in acid solutions. 16,17In basic solutions, insoluble Zn(OH) 2 is formed and this limits the reactivity of Zn(II).However, it is possible to reduce the formation of insoluble hydroxycompounds through the addition of liganting agents. 16The presence of the chloride ion (for which Zn(II) has great affinity 14 ) in the reaction environment is specially important because it allows the formation of soluble chemical species (ZnCl + , ZnCl 2 , ZnCl 3 -) able to react with polydentate ligands.Thus, we performed the treatment of 1 with Zn(II) in aqueous media and effected scanning reactions by two means: 1) At constant concentration (0.1 M), the reaction of 1 with ZnCl 2 was performed at different values of pH (from 1 to 7); and 2) At variable concentrations (from 0.06 to 0.12 M), H 3 L 2+ dihydrochloride was made to interact with 3Zn(OH) 2 •2ZnCO 3 .

Reaction of 1 with ZnCl 2 at variable pH
At constant concentration, we scanned, the reaction of 1 with ZnCl 2 every 0.5 units of pH through the use of infrared spectroscopy and X-Ray diffraction (Figure 1).We found that the action of Zn(II) ion changes the pKa values of 1.Thus, in the range of pH from 0 to 2.4 compound 2 is present.The ligand in 2 features the entire coordination center blocked by N-H bonds.In these reaction conditions, the Zn(II) ion assumes the form of tetrachlorozincate(2-). 18 At pH 2.4, compounds 2 and 3 are present in solution, but at higher pH's, 2 disappears and 3 predominates.In absence of any metallic ion, the neutral species of 1 (H 2 L + ← → HL + H + ) must predominate after pH 7. 11 However, we determine the existence of compound 5 at more acidic values of pH (4.5 to 6.4).The presence of the bidentate form of the ligand 1 in solution and its chelate coordination with the Zn(II) ion perhaps favor the formation of compound 5 in these acid conditions.However, total evaporation of the solutions at pH 5.6 -6.4 leads only to compound 4.
Presumably, the slow evaporation causes the increase of the chloride concentration and instead of compound 5, the complex 4 is obtained.
Reaction of H 3 L 2+ with 3Zn(OH) 2 •2ZnCO 3 at concentration variable Although the 3Zn(OH) 2 •2ZnCO 3 salt is practically insoluble in water, the presence of 1 in the form of H 3 L 2+ makes it possible the reaction of Zn(II).A slow acid-base reaction leads to produce the neutral form of 1 (HL) and makes Zn(II) become soluble.Thus, the concentration of Zn(II) in solution is always small and the ligand is in excess.We effected a set of reactions of H 3 L 2+ with 3Zn(OH) 2 •2ZnCO 3 at different concentrations of benzimidazole (from 0.06 to 0.12 M).In all cases, when the mixture was stirred for 24 hours, compound 4 was obtained.On the other hand, when the mixture was stirred for 30 minutes, the reaction yielded instead compound 5.Moreover, we found that the best conditions of reaction (good yields and excellent quality of crystallization) were achieved at benzimidazole concentrations of 0.08 M.

Infrared and Raman studies
The infrared and Raman studies confirm the presence of the Zn-compounds 2-5.Thus, the in plane mode vibrations in benzimidazoles are present between 419 and 1620 cm -1 19 and the characteristic signal for the in-plane vibration of the imidazole N-H is localized near 1590 cm -1 .
The in-plane N-H vibrations for 2 are shifted toward smaller frequencies (∆δ = 25 cm -1 ) compared to compounds 3-5 (δ = 1588 cm -1 ) and this makes evident the presence of strong hydrogen bond interactions. 19In contrast to complexes 2-4, where the C=N stretching vibration appears as a lone signal in the region of 1617-1624 cm -1 , compound 5 shows two signals (1624 and 1651 cm -1 ) that support the Zn penta-coordination.On the other hand, IR spectra of 1 and 3 show a signal at 1598 cm -1 attributed to in-plane bending vibrations of the NH 3 group, 20 while the absence of this signal in compounds 4 and 5 suggests the chelate coordination of HL ligand to Zn.Moreover, the typical NH 2 wagging vibrations for compounds 4 and 5 are found at 680 and 673 cm -1 , respectively, and support the chelate coordination in these compounds. 20,21The set of signals for the aromatic C-H and imidazolic N-H out-plane mode vibrations are characteristic for each of the Zn compounds 3-5 in the infrared spectra and therefore are useful to differentiate one another.Thus, for 3 the out-plane mode vibrations are grouped next to 751 cm -1 as strong, thin signals, in the case of 4-5 the corresponding signals are strong and coarse and are distributed in the region form 535 to 768 cm -1 .Nevertheless, the double coordination of 1 with the Zn atom and its minor symmetry causes a larger number of these signals for 5 (546, 609, 640, 711, 756, 771 cm -1 ) than for 4 (533, 627, 758, 769 cm -1 ).
In Raman spectra the Zn-Cl stretching vibrations for 2 and 3 are observed as single signals (286, and 284 cm -1 respectively) and are evidence that in these molecules the Zn-Cl bonds are symmetrically equivalent. 22For compound 4 the two Zn-Cl stretching vibrations are observed in 310 and 235 cm -1 and confirm the presence of two chlorine atoms bonded to Zn.On the one hand, for compound 5 the Zn-Cl stretching vibration (230 cm -1 ) appears at a lower frequency than in the case of 2-4.This result is in agreement with the penta-coordination of compound 5 and a longer Zn-Cl bond distance.Furthermore, two Zn-N stretching vibrations are observed in compounds 4 and 5 (424 and 490 cm -1 ) that make evident the chelate coordination of ligand HL in these compounds. 23

NMR studies in solution
The 13 C NMR spectra of compounds 2-5 have a symmetric behavior and only one set of signals were found for all aromatic carbons (Table 1).Thus, in all cases C5 and C6 have the same resonance.Compared to 1, the presence of N→Zn coordination bond on the imidazole nitrogen in compounds 3-4 causes a shift toward lower frequencies for C5 and C6 (∆δ = 3.7-3.1 ppm).However, in compounds 4 and 5, C4 and C7 have broad signals that are evidence of a dynamic behavior.It is known that the Zn complexes are characterized by a high coordinate flexibility due to presence of bond-breaking phenomena (Zn ← L ← → Zn + L). [24][25][26][27] Therefore, it is probable that in aqueous solution, compounds 3-5 undergo N→Zn bond-breaking phenomena at aromatic nitrogen atoms (Scheme 2).9][30][31][32][33][34] Thus, in compounds 3-5, it is possible that the free benzimidazole groups present an intermolecular proton transfer mechanism with the solvent (D 2 O) and this fact perhaps explains the high symmetry of their NMR spectra.When the solvent is evaporated of the NMR tubes with 3 or 5 complexes, the infrared spectra and X-ray diffraction of the solid residues show that these compounds have once more the original crystalline structure where the aromatic nitrogen atoms present the N→Zn coordination.This information corroborates the existence of N→Zn bond-breaking equilibrium of 3 and 5 in aqueous solutions.On the other hand, in 1 H NMR the methylene hydrogens (H1) resonances of compounds 4 and 5 are displaced toward lower frequencies (∆δ = 0.54-0.2ppm) with respect to compounds 2 and 3.This result confirms the coordination of the amine group with the Zn(II) ion in 4 and 5. Table 1. 13

X-Ray crystallography
The X-ray crystallography corroborates the molecular structure of 2-5 (Table 2) and shows the presence of strong intermolecular hydrogen bonds.Molecule 2 is not a coordination compound because all the coordinated centers in the 1H-benzimidazol-2-ylmethanamine are blocked by N-H bonds.However, the ZnCl   Compound 3 is mono-coordinated, the metal atom is bonded to an imidazolic nitrogen atom.In the unit cell there are two Zn complexes that are not symmetrically equivalent (Figure 3).In conclusion, the synthesis of compounds 2-5 has strong dependence on pH and concentration of the reactants.The coordination modes of Zn(II) with 1H-benzimidazol-2- ylmethanamine depend on the acid-base behavior of the ligand and the existence of the metallic ion in solution.The X-ray crystallography of 2-5 shows the presence of strong hydrogen bonds that produce pseudo-macrocyclic networks.The presence of the chloride ion in the crystalline structures is important since it maximizes the hydrogen bond interactions.The NMR studies suggest that compounds 3-5 have fluxional behavior in aqueous solution, where the N→Zn bonds present breaking phenomena.

Experimental Section
General Procedures.Water was freshly distilled and de-ionized before use.Melting points were measured on a Mel-Temp II apparatus and are uncorrected.The IR spectra and Raman were recorded on a Perkin-Elmer System Spectrum GX spectrophotometer.Mass spectra were recorded on JEOL MStation JMS-700 with FAB method and 3-nitrobenzyl alcohol (NBA) as matrix.Elemental analyses were determined on a Perkin-Elmer Series II CHNS/O analyzer 2400 instrument.NMR spectra were obtained on a JEOL GXS-400 MHz spectrometer in D 2 O solution.Chemical shifts (ppm) are relative to MeOH as external reference for 1 H and 13 C. pH measurements were obtained using a Radiometer-Copenhagen PHM 250 pH-meter equipped with an ORION combined ROSS pH-electrode.Calibration of the electrode system was performed with Radiometer-Copenhagen IUPAC standard buffers of pH 4.005, 7.000 and 10.012.Data was collected on a Bruker Smart 6000 diffractometer equipped with a CCD area detector (λ Mokα = 0.71073 Å, monochromar: graphite).Frames were collected via ω/φ-rotation (∆/ω = 0.3º) at 10 s per frame (program SMART). 36The measured intensities were reduced to F 2 without absorption correction (program SAINT-NT 37 ).Structure solution, refinement and data output were carried out with the SHELXTL-NT program package. 38The non-hydrogen atoms were refined anisotropically.All H atoms in compounds 4 and 5 were located in a difference Fourier map and refined isotropically.In compounds 2 (except H1, H3) and 3 (except H1, H16, H17, H1'), the H atoms were placed in geometrically calculated positions using a riding model.Although we examined the yield of compounds 2-5 varying concentration of the reagents or pH, we only show the best experimental procedure that we found for each Zn(II) compound.

4 2 - 4 R ( 18 )
anion takes part in the hydrogen bond network.It is interesting that only three Cl atoms in ZnCl 4 2-anion are acceptors of H atoms (Figure 2) and this fact is reflected in the Zn-Cl bond length.Thus, Zn1-Cl1 and Zn1-Cl2 statistically have (e.s.d.) the same bond lengths [2.317(1) and 2.297(1) Å respectively] and these are longer than Zn1-Cl3 [2.258(1) Å].These differences can be attributed to Cl1 and Cl2 having stronger intermolecular hydrogen bonds with N2-H2B and N1-H1 than the one Cl3 has with N3-H3.Finally, Cl4 does not act as acceptor of hydrogen atoms and the bond length Zn1-Cl4 is the shortest [2.233(1) Å].The H atoms are donated by ammonia and imidazole groups, and in the hydrogen bond pattern, three graph sets with pseudo-macrocyclic structure can be distinguished:4 involving atoms