Design, Synthesis and Characterization of a Bicompartmental bisthiosemicarbazone Ligand ^†

Abstract

In this work, we present the design and synthesis of the bisthiosemicarbazone ligand H₃L^Me by means of an iminic condensation reaction between 2-hydroxyisophthalaldehyde and 4-methyl-3-thiosemicarbazide. This ligand is bicompartmental, pentadentate [N₂S₂O] and potentially trianionic. The presence of a spacer constituted by a phenol group facilitates the coordination of transition metal ions, giving rise to a great variety of structures. To confirm the purity of the ligand, different characterization techniques were employed, including elemental analysis, mass spectrometry, infrared spectroscopy, and nuclear magnetic resonance. The acquisition of suitable crystals of H₃L^Me allowed us to analyze its structure through X-ray diffraction studies.

1. Introduction

Thiosemicarbazones and bisthiosemicarbazones are organic ligands whose skeletons have donor atoms such as nitrogen and sulfur. These compounds are obtained by the reaction of a thiosemicarbazide with aldehydes or ketones [1]. The design and synthesis of this type of ligands has been extensively studied in recent decades due to their important properties: ion sensing [2], catalytic [3], magnetic [4], pharmaceutical, and biological (antiviral, radioprotective, anti-inflammatory, antibacterial, antifungal and antitumoral) [5].

With all this in mind, the coordination chemistry of these types of compounds and, therefore, their biological applications have been of great interest. Thus, in this work we report the design, synthesis, and characterization of a bisthiosemicarbazone ligand, H₃L^Me, a potential precursor of dinuclear metal-derived complexes.

2. Experimental Section

The bisthiosemicarbazone ligand H₃L^Me synthesis was carried out by means of an imine condensation reaction between 2-hydroxyisophthalaldehyde and 4-methyl-3-thiosemicarbazide in ratio 1:2, using absolute ethanol as a solvent (Figure 1). To promote the formation of the imine bond, acid catalysis was used by adding p-toluensulfonic acid. The reaction mixture was refluxed for 4 h using a Dean−Stark trap to remove the released water.

Finally, the bisthiosemicarbazide ligand was isolated as a yellow solid, which was characterized by the usual techniques in the solid state and in solution.

H₃L^Me: Yield 0.722 g, (90%). Elemental analysis, Calc. for C₁₂H₁₆N₆OS₂: C, 44.4; H, 5.0; N, 25.9; S, 19.8. Found: C, 44.5; H, 5.0; N, 25.7; S, 19.9%. MS ESI+ (m/z): 325.1 [H₃L^Me+H]. IR (KBr, cm⁻¹): ν(O-H) 3360 (m), ν(N-H) 3163 (m), ν(C=N + C-N) 1611 (m), 1541 (mf), 1497 (m), ν(C-O) 1231 (f) ν(C=S) 1094 (m), 800 (mf), υ(N-N) 1051 (d) RMN ¹H (400 MHz, dmso-d₆) δ 11.51 (s, 2H), 9.95 (s,1H), 8.51 (d, J = 4.7 Hz, 2H), 8.37 (s, 2H), 7.80 (d, J = 7.8 Hz, 2H), 6.98 (t, J = 7.7 Hz, 1H), 3.02 (s, 6H). RMN ¹³C (400 MHz, DMSO-d₆): δ/ppm, 178.50 (C=S), 155.40 (C-O), 141.59 (C=N), 130.78–120.73(C-Ar), 31.80 (CH₃).

Crystallographic Data

H₃L^Me·CH₃OH: C₁₂H₁₆N₆OS₂; MW: 356.47 g·mol⁻¹; crystal dimensions: 0.12 × 0.03 × 0.02 mm; monoclinic; P2_1/c; a = 13.2462 (7), b = 19.1436 (9), c = 6.8852 (4) Å; α = 90; β = 99.102(4), γ = 90 ⁰; V = 1723.96(16) ų; z = 2; μ = 2.96 mm⁻¹; measured reflections = 28545; independent reflections [R_int] = 3149 [0.165]; R = 0.078; wR = 0.191.

3. Results and Discussion

The bisthiosemicarbazone ligand H₃L^Me can be described as bicompartmental, potentially trianionic, and pentadentate [N₂S₂O], showing two [NS] binding domains separated by a short spacer with an oxygen donor atom. The ligand H₃L^Me was fully characterized by the usual techniques for organic compounds.

3.1. IR Spectroscopy

Infrared spectra were obtained in the solid state using the KBr pellet transmission technique in the range 4000–500 cm⁻¹ (Figure 2). Band assignments were carried out based on the literature [6].

In these spectra, the absence of the band corresponding to the carbonyl group, υ(C=O) of the precursor 2-hydroxyisophthalaldehyde around 1700 cm⁻¹, and the appearance of new bands around 1610 cm⁻¹ attributed to the imine υ(C=N) bonds, confirming the formation of the ligand H₃L^Me, should be highlighted.

3.2. X-ray Diffraction

The recrystallization in methanol of solid H₃L^Me allowed us to obtain yellow crystals suitable for X-ray diffraction studies. The asymmetric unit of the H₃L^Me ligand consists of a ligand molecule solvated by a methanol molecule (Figure 3). The main bond distances and angles given in

Table 1. Selected bond length (Å) for H₃L^Me.

Main Bond Distances (Å)
C3=N3	1.291	C10=N4	1.278
N2-N3	1.387	N4-N5	1.383
C2=S1	1.682	C11=S2	1.694
C2-N1	1.333	C11-N6	1.326
C9-O1	1.353

and

Table 2. Selected bond angles (⁰) for H₃L^Me.

Main Bond Angles (°)
N1-C2-N2	117.2	N6-C11-N5	116.6
N1-C2=S1	124.4	N6-C11=S2	124.8
N2-C2=S1	118.4	N5-C11=S2	118.6
N3=C3-C4	123.3	N4=C10-C8	120.3
C2-N2-N3	122.1	C11-N5-N4	119.3
C3=N3-N2	114.5	C10=N4-N5	115.5

are in the expected range for bisthiosemicarbazone ligands [7].

The ligand shows an E configuration with respect to the imine bonds and an anti conformation with both branches arranged on opposite sides. This arrangement is conditioned by the existence of intramolecular hydrogen bonds between the imine nitrogen and the hydroxyl group of the spacer. In addition, there are intramolecular hydrogen bonds between the phenolic hydrogen and the oxygen of the solvating molecule, as well as between the thioamide NH and the methanol oxygen atom, and between the OH group of the solvation molecule and the thioamide sulfur of an adjacent ligand. These interactions result in the ligand molecules being connected throughout the crystal lattice (Figure 4).

4. Conclusions

The new bisthiosemicarbazone ligand H₃L^Me has been synthesized and isolated with high purity and yield. The X-ray diffraction study of the crystals that were obtained allowed us to know the structure of the ligand. The crystallographic studies revealed that the [NS] donor atoms are oriented in different directions in both ligand branches, indicating a conformational rotation to obtain metal-derived complexes.