A Novel Centrosymmetric Fe(III) Complex with Anionic Bis-pyrazolyl-s-triazine Ligand; Synthesis, Structural Investigations and Antimicrobial Evaluations

Abstract

Reaction of 2,4-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methoxy-1,3,5-triazine (MBPT) pincer ligand with FeCl₃ in acidic medium (1:1 v/v) afforded the [Fe(BPT)Cl₂(CH₃OH)] complex of the hydrolyzed monobasic ligand: 4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazin-2(1H)-one (HBPT). In this complex, the Fe(III) ion is hexacoordinated with one anionic pincer ligand unit (BPT⁻¹), two chloride ions, and one coordinated methanol molecule. It crystallized in the monoclinic crystal system and centrosymmetric P2₁/c space group with Z = 2 and unit cell parameters of a = 7.309(2) Å, b = 25.461(8) Å, c = 9.918(3) Å and β = 102.646(7)°. The structure of this complex is stabilized by C–H…Cl intramolecular hydrogen bonding interactions with donor acceptor distances ranging from 3.577(3)–3.609(3) Å while its supramolecular structure is controlled by intermolecular O–H…O, O–H…N, and C–H…Cl hydrogen bonding interactions. Hirshfeld analysis of molecular packing indicates that the percentages of the Cl…H, C…O, O…H, C…C, H…C, and N…H contacts are 21.1, 1.7, 10.2, 2.1, 8.6, and 10.4%, respectively. The nature and relative strength of the different coordination interactions in the [Fe(BPT)Cl₂(CH₃OH)] complex are discussed based on atoms in molecules theory. Antimicrobial evaluations indicated that the [Fe(BPT)Cl₂(CH₃OH)] complex showed moderate antibacterial and antifungal activities compared to amoxicillin and ampicillin antibiotics as standard drugs.

1. Introduction

Iron is considered as a readily available and cheap element with little hazardous effects on the environment. Iron-containing compounds play a crucial role in ammonia production by the Haber–Bosch process and in homogenous molecular catalysis [1,2,3,4]. Iron has a great importance in a variety of biological systems of mammals and other simple microorganisms. Generally, it is considered to have low toxicity, but high iron concentrations in living cells can cause some harmful effects, as can iron deficiency [5,6,7]. High iron levels in the body can catalyze the generation of harmful free radicals [8,9]. In this regard, powerful chelators can be used to control this risk by controlling iron reactivity. Also, iron (III) complexes with N-donor ligands have been reported to have promising anticancer activity [10,11,12,13].

2,4-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methoxy-1,3,5-triazine (MBPT, Figure 1) pincer ligand is a powerful nitrogen tridentate chelator that can form metal complexes by the reaction with a diversity of metal salts [14,15,16]. The self-assembly of this functional ligand with metal salts such as Ni(II), Mn(II), Co(II), Zn(II) and Cd(II) comprising different anions (Cl⁻, NO₃⁻, ClO₄⁻) has afforded a variety of mononuclear homo and heteroleptic metal (II) complexes with coordination numbers varying from five to eight [14,15,16]. Using the same technique, the same ligand underwent metal ion-mediated hydrolysis in the presence of CuCl₂ or Cu(ClO₄)₂, leading to the formation of one-dimensional Cu(II) coordination polymers [17]. Similar hydrolytic reactions were detected in the presence of other metal (II) salts such as ZnCl₂, PdCl₂, and PtCl₂ [15,16,18]. It was confirmed that the role of the metal ion is to increase the acidity of the water molecule, which eases the hydrolytic reaction, as was confirmed by the acid-mediated hydrolysis of MBPT in the presence of aqueous hydrochloric acid solution to afford HBPT (Figure 1) [17]. In continuation of this work, we tested the reaction of this pincer ligand with FeCl₃ in acidic medium. The structure of the new [Fe(BPT)Cl₂(CH₃OH)] complex was confirmed using elemental analysis, FTIR spectra, and single crystal X-ray diffraction. Evaluation of the antimicrobial activity of the studied complex was also presented.

2. Materials and Methods

2.1. Materials and Physical Measurements

Chemicals were purchased from the Sigma-Aldrich Company (Chemie GmbH, 82024 Taufkirchen, Germany). CHN analyses were performed using a Perkin Elmer 2400 Elemental Analyzer (PerkinElmer, Inc., 940 Winter Street, Waltham, MA, USA). Iron content was determined using the Shimadzu atomic absorption spectrophotometer (AA-7000 series, Shimadzu, Ltd., Tokyo, Japan). An Alpha Bruker spectrophotometer (Billerica, MA, USA) was used to measure the FTIR spectra in KBr pellets (Figure S1, Supplementary Data).

2.2. Synthesis

2.2.1. Synthesis of S-Triazine-Based Ligand

The ligand MBPT was prepared as previously reported [14] (Supplementary Data, Method S1, Figures S2 and S3).

2.2.2. Synthesis of [Fe(BPT)(CH₃OH)Cl₂] Complex

The studied complex was synthesized using a self-assembly technique by mixing the acidified aqueous (2 drops of 1:1 v/v HCl) solution of FeCl₃ (1 mmol, 162 mg) with an equimolar amount of MBPT ligand in ethanol. The mixture was left for slow evaporation and the resulting brown crystals were collected by filtration.

Yield; C₁₈H₂₄N₈Fe₂Cl₆, 69%. Anal. Calc. C, 37.95%; H, 4.09%; N, 22.13%; Cl, 16.00%; Fe, 12.60%. Found: C, 37.80%; H, 4.01%; N, 21.98%; Cl, 15.88%; Fe, 12.49%; IR (KBr, cm⁻¹): 3454, 1630, 1606, 1586(Sh), 1475 (Figure S1, Supplementary Data).

2.3. Crystal Structure Determination

The crystal structure of the [Fe(BPT)(CH₃OH)Cl₂] complex was determined by using a Bruker D8 Quest diffractometer employing SHELXTL and SADABS programs [19,20,21]. Hirshfeld calculations were performed using the Crystal Explorer 17.5 program [22,23,24,25,26].

2.4. Antimicrobial Studies

The antimicrobial activities of the [Fe(BPT)(CH₃OH)Cl₂] complex against different microbes were determined following the reported method [27]. More details regarding the antimicrobial assay are found in Supplementary Data (Method S2).

2.5. Atoms in Molecules (AIM) and Natural Charge Calculations

Gaussian 09 [28] software was used for all single point calculations using the MPW1PW91/TZVP [29] method. Charge population and atoms in molecules (AIM) analyses were performed using NBO 3.1 [30] and Multiwfn [31] programs, respectively. Based on literature, s-triazine pincer ligands are well known to have a weak ligand field and form only high spin complexes due to the electron-deficient characters of the s-triazine moiety. Hence, the calculations were performed based on the fact that the presented complex was a high spin iron (III) complex with a total spin of 5/2 and sextet multiplicity [14].

3. Results

Reaction of the bis-pyrazolyl-s-triazine (MBPT) ligand with ferric chloride in acidic medium afforded a novel Fe(III) pincer complex. It was observed that the reaction proceeded with O-demethylation of the methoxy group [32,33] and furnished the hydroxy-s-triazine derivative 4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazin-2(1H)-one (HBPT), which underwent in situ reaction with FeCl₃ and afforded the [Fe(BPT)(CH₃OH)Cl₂] complex in moderate yield. In this complex, the hydrolyzed ligand (HBPT) acted as a mononegative tridentate NNN-pincer chelate (Scheme 1). The structure of the [Fe(BPT)(CH₃OH)Cl₂] was confirmed with the aid of elemental analysis, FTIR spectra, and single crystal X-ray diffraction.

4. Discussion

4.1. Structure Description

The molecular structure of the heteroleptic [Fe(BPT)(CH₃OH)Cl₂] complex is shown in Figure 2. This Fe(III) complex crystallized in the monoclinic crystal system and P2₁/c space group with Z = 2 and unit cell parameters of a = 7.309(2) Å, b = 25.461(8) Å, c = 9.918(3) Å, and β = 102.646(7)°, where the asymmetric unit contained one molecular formula. The most relevant geometric parameters are listed in

Table 1. Crystal data and structure refinement for the [Fe(BPT)(CH₃OH)Cl₂] complex.

Empirical formula	C14H18Cl2FeN7O2
Formula weight	443.10 g/mol
Temperature	115(2) K
Wavelength	0.71073 Å
Crystal system	monoclinic
Space group	P21/c
Unit cell dimensions	a = 7.309(2) Å	α = 90°
	b = 25.461(8) Å	β = 102.646(7)°
	c = 9.918(3) Å	γ = 90°
Volume	1800.9(9) Å3
Z	4
Density (calculated)	1.634 g/cm3
Absorption coefficient	1.160 mm−1
F(000)	908
Crystal size, mm3	0.18 × 0.19 × 0.22
Theta range for data collection	2.25 to 25.30°
Index ranges	−8 ≤ h ≤ 8, −30 ≤ k ≤ 30, −11 ≤ l ≤ 11
Reflections collected	20,165
Independent reflections	3277 [R(int) = 0.0346]
Completeness to theta	99.90%
Refinement method	Full-matrix least-squares on F2
Data/restraints/parameters	3277/0/244
Goodness-of-fit on F2	1.083
Final R indices [I > 2sigma(I)]	R1 = 0.0339, wR2 = 0.0860
R indices (all data)	R1 = 0.0381, wR2 = 0.0881
Largest diff. peak and hole	1.630 and −0.563
CCDC no.	2090699

.

In this neutral complex, the Fe(III) was hexacoordinated with a distorted octahedral coordination environment. The Fe(III) was coordinated with one mononegative tridentate BPT⁻¹ and one coordinated chloride ion in the basal plane of the distorted octahedron, while the axial positions were occupied by one chloride anion and a coordinated methanol molecule. Similar to other M(II)–MBPT pincer complexes [14,15,16], there were three Fe–N interactions with the organic pincer ligand where the Fe–N_(s-triazine) was generally shorter (Fe1–N5: 2.079(2) Å) than any of the Fe–N_(pyrazole) bonds (Fe1–N1: 2.154(2) Å and Fe1–N3: 2.156(2) Å). The equatorial Fe1–Cl1 (2.255(8) Å) was slightly shorter than the axial Fe1–Cl2 (2.302(9) Å), while the Fe1–O2 bond with the coordinated methanol was 2.112(2) Å. As calculated by the continuous shape measure (CShM) tool, the values of the CShM were 2.45 and 13.72 against the perfect octahedron and trigonal prism, respectively indicating a slightly distorted octahedral rather than a trigonal prism [34,35,36,37]. The triazine ring itself was not perfectly planar as indicated from the torsion angles where the maximum deviation from planarity was 7.4(3)° for C11–N6–C13–N7 atoms. The mean plane passing through the triazine ring created angles of 2.96 and 7.24° with the pyrazolyl moieties N4C8C7C6N3 and C3C2C1N1N2, respectively. The reason for these twists could be attributed to the small size of Fe(III) and its high charge density, along with the steric hinder between the coordinated pyrazolyl moieties [15].

The structure of this complex was stabilized by C4–H4C…Cl1 and C9–H9B…Cl1 intramolecular hydrogen bonds with donor acceptor distances of 3.609(3) and 3.577(3) Å, respectively. On the other hand, its supramolecular structure was controlled by intermolecular O2–H2A…O1, O2–H2A…N6, C2–H2…Cl2, and C14–H14C…Cl2 hydrogen bonding interactions with donor acceptor distances of 2.694(3), 3.181(3), 3.605(3), and 3.735(4) Å, respectively. A list of hydrogen bond details is given in

Table 2. Bond lengths (Å) and angles (°) for the [Fe(BPT)(CH₃OH)Cl₂] complex.

Bond	Distance	Bond	Distance
Fe1–N5	2.079(2)	Fe1–N3	2.156(2)
Fe1–O2	2.112(2)	Fe1–Cl1	2.2550(8)
Fe1–N1	2.154(2)	Fe1–Cl2	2.3020(9)
Bond	Angle	Bond	Angle
N5–Fe1–O2	83.02(8)	N1–Fe1–Cl1	106.04(6)
N5–Fe1–N1	73.31(8)	N3–Fe1–Cl1	106.46(6)
O2–Fe1–N1	86.24(8)	N5–Fe1–Cl2	93.35(6)
N5–Fe1–N3	73.02(8)	O2–Fe1–Cl2	175.69(6)
O2–Fe1–N3	85.46(8)	N1–Fe1–Cl2	94.96(6)
N1–Fe1–N3	146.04(8)	N3–Fe1–Cl2	91.28(7)
N5–Fe1–Cl1	170.77(6)	Cl1–Fe1–Cl2	95.87(3)
O2–Fe1–Cl1	87.76(6)
Fe1–N5	2.079(2)	Fe1–N3	2.156(2)
Fe1–O2	2.112(2)	Fe1–Cl1	2.2550(8)
Fe1–N1	2.154(2)	Fe1–Cl2	2.3020(9)

. In addition, presentation of the packed molecular units via these noncovalent interactions is shown in Figure 3.

4.2. Quantitative Analysis of Molecular Packing

Hirshfeld analysis is a simple tool to investigate the molecular packing in the crystal structure at both the qualitative and quantitative levels. In d_norm surfaces shown in Figure 4, there were many red regions representing contacts with shorter distances than the van der Waals radii (vdWs) sum of the interacting atoms. On the other hand, the blue and white regions were related to intermolecular contacts having longer and equal interaction distances than the vdWs radii sum of the interacting atoms, respectively. For simplicity, the most significant contacts are labeled A to F, which correspond to Cl…H, C…O, O…H, C…C, H…C, and N…H interactions, respectively.

The hydrogenic H…H intermolecular interactions were the most abundant among the other contacts. They contributed 40.9% to the whole fingerprint area (Figure S4; Supplementary Data). There were no red regions related to the H…H interactions, indicating longer or equal distances compared to twice the vdW radii of hydrogen atoms. On the other hand, the percentage contributions of the Cl…H, C…O, O…H, C…C, H…C, and N…H contacts were quite less. Their percentages were 21.1, 1.7, 10.2, 2.1, 8.6, and 10.4%, respectively. All these contacts appeared as red regions in the d_norm map (Figure 4).

The shortest contact distances were 2.656Å (Cl2…H2), 3.056 Å (C11…O1), 1.714 Å (O1…H2A), 2.685 Å (H4A…C13), 3.331 Å (C13…C3), and 2.615 Å (N7…H5A). A summary of these short contacts and their interaction distances is found in

Table 3. Summary of the intermolecular interactions and the corresponding shortest interaction distances.

Contact	Distance	Contact	Distance
O1…H2A	1.714	C11…O1	3.056
O1…H4A	2.595	Cl1…H9C	2.814
H4A…C13	2.685	Cl2…H2	2.656
C11…C2	3.373	Cl2…H7	2.713
C13…C3	3.331	Cl2…H14C	2.685
N7…H5A	2.615

. In the fingerprint plots shown in Figure 5, the d_e and d_i are distances from a point on the surface to the nearest nucleus outside and inside the surface, respectively. Hence, the pattern of the fingerprint plot gives strong indication of the strength of interaction. The majority of these interactions appeared as sharp spikes in their fingerprint plots, indicating that these contacts were the most important and had short interaction distances (Figure 5). Also, the total area of the fingerprint plot represents the percentage of the intermolecular interactions that occurred in the crystal. As a result, the decomposition of the fingerprint plot shown in Figure 5 gives the percentages of each intermolecular interaction (Figure S4; Supplementary Data).

4.3. NBO and AIM Studies

The natural charges of the ligand groups and the iron atom were calculated in order to determine the number of charge transferences from the ligand groups as Lewis bases to the Fe(III) as Lewis acid. The charge at the Fe atom decreased to 0.9509 e instead of +3 for the isolated Fe(III) ion. Hence, the amount of negative electron density transferred to Fe(III) from the ligand groups was 2.0492 e. The equatorial chloride (0.5571 e) transferred higher negative electron density to the Fe(III) than the axial one (0.5913 e). The amount of electron density transferred from the mononegative tridentate organic N-chelate to the Fe(III) was 0.7424 e, while the corresponding value for the coordinated methanol was 0.1583 e.

On the other hand, the atom–atom interactions could be classified into two main categories, which were the closed shell and sharing interactions [38,39,40,41]. Based on the topology analysis of the atoms in molecules (AIM) theory presented in

Table 4. Atoms in molecules topology parameters of the [Fe(BPT)(CH₃OH)Cl₂] complex.

Bond	ρ(r)	G(r) a	V(r) b	Eint	H(r) c	V(r)/G(r)
Fe1–N5	0.0810	0.1030	−0.1250	39.21	−0.0220	1.21
Fe1–N1	0.0584	0.0728	−0.0803	25.21	−0.0075	1.10
Fe1–N3	0.0580	0.0715	−0.0787	24.70	−0.0072	1.10
Fe1–Cl1	0.0720	0.0730	−0.0898	28.18	−0.0168	1.23
Fe1–Cl2	0.0687	0.0597	−0.0762	23.91	−0.0165	1.28
Fe1–O2	0.0421	0.0795	−0.0791	24.82	0.0004	0.99

^a Kinetic energy density (a.u.). ^b Potential energy density (a.u.). ^c Total energy density (a.u.).

, the Fe–N_(s-triazine) bond (Fe1–N5) had higher electron density (ρ(r)) than any of the Fe–N_(pyrazole) bonds (Fe1–N1 and Fe1–N3). Hence, the Fe–N_(s-triazine) was stronger and with higher covalent characters than the Fe–N_(pyrazole) bonds, which was further confirmed by the negative H(r) values and V(r)/G(r) > 1. In contrast, the Fe–O bond with the coordinated methanol had low ρ(r), positive H(r) value, and V(r)/G(r) ~ 1, indicating little covalent character of this bond [38,39,40,41].

4.4. Antimicrobial Studies

The biological activity of the [Fe(BPT)(CH₃OH)Cl₂] complex was evaluated against selected Gram-positive (Staphylococcus aureus, Bacillus cereus, and Bacillus subtilis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria as well as the fungus Candida albicans. The inhibition zone diameters were found to be in the range 0.9–1.0 mm at 10 μg/mL of the [Fe(BPT)(CH₃OH)Cl₂] complex. Similar Fe(III) complexes with mono- and bis-pyrazolyl s-triazine ligands showed larger inhibition zone diameters (12–25 mm) against the same microbes [42]. It is worth concluding that the antimicrobial activities depend not only on the ligand and nature of the coordination environment around the metal ion but also on the type of substituent attached to the triazine moiety.

In addition, the Minimum Inhibitory Concentrations (MICs) were determined against these microbes (

Table 5. The MIC values (mM/L) of the [Fe(BPT)(CH₃OH)Cl₂] complex against different microbes compared to some antibiotics.

Microbe	[Fe(BPT)(CH3OH)Cl2]	Amoxicillin	Ampicillin
St. aureus	6.8	2.7	2.7
B. cereus	7.9	2.1	2.1
B. subtilis	7.3	2.7	3.6
E. coli	7.9	2.7	3.6
P. aeruginosa	7.3	2.1	2.9
C. albicans	6.2	3.4	4.3

). The results indicated broad spectrum antimicrobial action against these microbes with MIC values of 6.8, 9.7, 7.3, 7.9, 7.3, and 6.2 mM/L. The results indicated moderate antibacterial and antifungal actions of the [Fe(BPT)(CH₃OH)Cl₂] complex compared to the standard antibiotics amoxicillin and ampicillin.

5. Conclusions

A new hexacoordinated [Fe(BPT)Cl₂(CH₃OH)] pincer complex was synthesized by the reaction of 2,4-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methoxy-1,3,5-triazine (MBPT) with FeCl₃ in acidic medium. During the complexation process in an acidic medium, the O-demethylation of the methoxy group occurred and furnished the hydroxy-s-triazine derivative; 4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazin-2(1H)-one (HBPT). The latter underwent complexation with FeCl₃ as an anionic NNN-pincer ligand coordinating the Fe(III) by one short Fe–N_(s-triazine) and two equidistant Fe–N_(pyrazole) bonds. The hexa-coordination environment was completed by two chloride ions and one methanol. The [Fe(BPT)Cl₂(CH₃OH)] complex had moderate antimicrobial activity against some selected microbes. Hirshfeld analysis was used to quantify the different intermolecular contacts while atoms in molecules (AIM) topology parameters were used to describe the nature and strength of coordination interactions in the [Fe(BPT)Cl₂(CH₃OH)] complex.