1. Introduction

The N-alkylamino phenothiazine derivatives (NPTZs) including chlorpromazine (CP) are biologically active heterocyclic compounds. Structurally, CP is a phenothiazine substituted with chlorine and tert-alkylamine groups at 2 and 10 positions, respectively (Fig. 1). The NPTZ derivatives find extensive applications in the field of medicine as antipsychotic, anxiolytic, antiemetic and inodilationdrugs[1-3].

Figure 1. Molecular structure of chlorpromazine hydrochloride

Previously, some studies of transition metal-NPTZ complexes have been reported by several workers[4-16]. Keshavan and co-workers[4-7] have synthesized and characterized compounds of selected NPTZs with molybdenum(IV), tungsten(IV), ruthenium(II/III) and copper(II). Keshavan and Janardhan[7], and Gowda and Jayarama[8] have reported mononuclear copper(II) and zinc(II) complexes of NPTZs. Kroener et al.[9] have studied the X-ray crystal structures of some cis- andtrans-bis(2,2′-bipyridine)-bis(phenothiazine-S)ruthenium(II) hexaflurophosphates. Made Gowda et al. have previously studied the synthesis and characterization of some coordination compounds of NPTZs with rhodium(II/III), rhenium(VII), iridium(III/IV), molybdenum(IV/V), zinc(II), palladium(II) and mercury(II)[10-16]. Chaitanya Lakshmi et al have reported transition metal-pyridoxine complexes[17-19]. We here report the synthesis and characterization of four transition metal complexes with CP.HCl as the main ligand.

2. Experimental

2.1. Materials

Metal salts, zinc bromide, cadmium bromide, cadmium iodide and mercuric bromide, and the ligand, chlorpromazine hydrochloride (CP·HCl; 99% pure) (Aldrich/Sigma Chemical Company) were used as supplied.

All solvents such as methanol, ethanol, diethyl ether, dimethyl sulfoxide, dimethyl formamide and DMSO-d₆ (Cambridge isotope laboratories Inc.) were of ACS reagent grade and were used without further purification. Double distilled water was used in all preparations.

2.2. Physical Measurements

Elemental analyses of complexes were performed by Microanalysis Laboratory, University of Illinois, Urbana-Champaign, IL. Molar conductance was determined with the Conductance-Resistance meter. UV-Visible spectra were recorded on a Shimadzu UV1601 spectrophotometer. The infrared spectra were recorded on a Shimadzu FTIR 8400 spectrometer using potassium bromide pellets. ¹H-NMR spectra were recorded on a JEOL-300MHz FT-NMR spectrometer in DMSO-d₆. Mass magnetic susceptibilities of the complexes were measured at room temperature with a Johnson Matthey magnetic susceptibility balance which uses HgCo(SCN)₄ as a calibrant.

2.3. General Synthesis of Complexes

A solution of the transition metal salt (x mmol) (ZnBr_2, CdBr₂, CdI₂ and HgBr₂) dissolved in a minimum volume of MeOH was slowly added with stirring to a concentrated methanolic solution of CP.HCl (2x mmol) and refluxed overnight. Each reaction mixture was cooled overnight at 0℃ and the precipitated product isolated by suction filtration through a medium-glass fritted funnel. The product was washed with small amounts of cold water first followed by methanol, air-dried, and dried in vacuo over anhydrous CaSO₄ in a desiccator. Each crude product was recrystallized twice from a hot saturated solution of the crude sample in methanol. The yield was determined.

3. Results and Discussion

The elemental analysis data listed in Table 1 show that the theoretical values are in agreement with the experimental ones. Physical properties of the new metal-CP.HCl complexes are presented in Table 2. Complexes are colored, microcrystalline, and relatively stable at room temperature with percent yields ranging from 71 to 93. The complexes are slightly soluble in common polar solvents such as MeOH and readily soluble in DMF and DMSO. All complexes except Zn(II) complex are insoluble in water.

The stoichiometric reactions involved in the complex formation are represented by the equations (1) and (2) below.

(1)

(2)

In the reaction for the formation of Hg(II) complex (eq. (2)), the larger Hg(II) ion as a soft acid tends to preferentially coordinate with the soft base Br⁻ as compared to the relatively harder Cl⁻ ion of the ligand. The molecular formulations and structures of the complexes were determined on the basis of elemental analysis, molar conductance, UV-Vis, IR, and NMR data.

Table 1. Elemental data of the metal–CP·HCl complexes

Table 2. Physical properties of the metal–CP·HCl complexes

The molar conductances for the complexes, measured in DMF and acetonitrile solutions, presented in Table 2 indicate that all complexes behave as 1:1 electrolytes (except CdI₂ complex which has 1:2 ionic ratio). Magnetic data of the complexes differ from the normal behavior of the d¹⁰ metal ions, Zn(II), Cd(II) and Hg(II), which are probably due to impurities[20]. The molecular formulations listed in Table 1 show that each complex contains a metal center and two chlorpromazine hydrochloride molecules as principal ligands. The other ligands include bromide and iodide ions. Additionally, complexes of CdBr₂ and HgBr₂ contain one and two H₂O molecules, respectively, as water of hydration.

The UV-Visible spectral data of the ligand (CP.HCl) and its complexes are presented in Table 3. The maximum absorption band at 254.50 nm for CP.HCl with a high molar absorptivity (ε = 1.69 × 10⁴ M^–1 cm^–1) suggesting a π→π^* transition is shifted for the metal-CP.HCl complexes to a lower wavelength with high varying molar absorptivities ( ε = (0.595 – 4.07) 10⁴ M^–1 cm^–1) indicating intraligand transitions of the π→π^* type that undergo hypsochromic shifts, confirming the metal-CP complexation[15-23].

Relevant IR absorption frequencies of the CP.HCl ligand and its metal complexes are presented in Table 4. In the uncomplexed CPHCl, the presence of a broad band in the 2000-2730 cm^-1 range is assigned to the interaction of the quaternary ammonium ion, (R₃NH)⁺ ion with a halide ion[12-15,21,22]. In the IR spectra of the metal-CP.HCl complexes, this band has shifted with diminished intensity suggesting that the exocyclic N atom of the alkylamino group is indirectly involved in coordination with the metal center. A band observed in the 3000-2800 cm^-1 region in the spectrum of CP.HCl may be assigned to the heterocyclic nitrogen atom carrying an alkyl amine side chain[21,22]. This band of CP.HCl shows a shift upon complexation suggesting its coordination to the metal(II) center[10-14]. In addition, CdBr₂ and HgBr₂ complexes show a broad band in the 3250-3560 cm^-1 region, supporting the hydrogen bonded OH interactions of the water of hydration. The Hg(II) complex spectrum shows that bands in the 600-700 cm^-1 and 715-740 cm^-1 regions, attributable to the heterocyclic C-S-C modes, undergo a shift, suggesting heterocyclic sulfur atom as a coordination site[12,15,22]. The ¹H NMR data for the ligand, CP.HCl, and its complexes are presented in Table 5. Comparing the absorption peaks/multiplets and the chemical shifts of the uncomplexed ligand with those of corresponding complexes, it could be inferred that some of the resonance signals experience shifts upon complexation. Especially, in the free CP.HCl ligand, the broad singlet which occurs far down field (δ 10.80), attributable to the exocyclic (R₃NH)⁺ proton, has shifted upfield on complexation indicating a change in this proton environment. This indirectly supports the existence of intramolecular hydrogen bonding between (R₃NH)⁺ and X^- of the MX₃ moiety[12,15,24].

Table 3. UV-Visible spectral data of the metal–CP·HCl complexes Complex/Ligand λmax (nm) Molar absorptivity (104, M–1 cm–1) Transition CP.HCl 254.50 1.69 π→π* ZnBr2(CP.HCl)2 252.50 1.25 π→π* CdBr2(CP.HCl)2.H2O 239.50 4.07 π→π* CdI2 (CP.HCl)2 255.50 1.12 π→π* HgBr2(CP.HBr)2.2H2O 237.50 0.595 π→π*

Table 4. Important IR absorptions of CP.HCl and its metal complexes Complex/ Ligand Absorption of (R3NH+) (cm-1) Absorption of (>N-R1) (cm-1) Absorption of (C-S-C) (cm-1) Absorption of (OH) (cm-1) CP.HCl 2730-2000 3000-2800 750 - ZnBr2 (CP.HCl)2 2900-2750 3100-2930 754 - CdBr2 (CP.HCl)2.H2O 2820-2600 3200-2860 754 3550-3250 CdI2 (CP.HCl)2 2810-2640 3200-2900 752 - HgBr2 (CP.HBr)2.2H2O 2820-2675 3200-2940 752 3600-3230

Table 5. 1H-NMR data of CP.HCl and its metal complexes*

Crystals of sufficient quality required to permit x-ray crystallographic analysis of the complexes could not be grown. Based on the discussed analytical data, tentative square pyramidal structures have been proposed for the complexes (Fig. 2.a-2.c). Similar structures have been reported for other phenothiazine-transition metal complexes[12-15,24]. A square pyramidal geometry around each M(II) metal center (sp³d hybridized), due to the steric constraints of the bidentate ligand not favoring a trigonal bipyramidal arrangement, involves two CP.HCl ligands and a monodentate bromide ion. With the relatively hard acids, Zn(II) and Cd(II) (Fig. 2.a), the CP.HCl binds through its heterocyclic N atom (as a hard base) directly and through the exocyclic N atom indirectly through the H-bonding with a halide ion. The scorpion tail like N-alkylamino group with its flexible bending mode is well suited for this kind of intramolecular H-bonding in NPTZs. The two protonated (CPH⁺) ligands coordinate to the MX₃ unit of the compound through two N atoms resulting in a square planar MX₂N₂ unit, which along with an axial M-X bond represents a square-pyramidal geometry for each complex. In the [HgBr(C₁₇H₁₉ClN₂S.HBr)₂]Br.2H₂O complex (Fig. 2.b), the relatively soft acid, Hg(II) binds to the CP ligand through its heterocyclic S atom (as a soft base) directly and through the exocyclic N atom indirectly through its H-bonding with a halide ion. In the [Cd(C₁₇H₁₉ClN₂S.HCl)₂]I₂ complex (Fig. 2.c), the Cd(II) center with an sp³ hybridization has a tetrahedral environment around it[14,15]. Similar transition metal complex structures have been reported in the literature[10-15].

Figure 2a. Proposed square pyramidal structure for the complex ion, [MBr(CP.HCl)2]+, where R = -C3H6, M = Zn(II) or Cd(II) and x = 0 for Zn(II) and 1 for Cd(II)

Figure 2b. Proposed square pyramidal structure for the complex ion, [HgBr(CP.HBr)2]+

Figure 2c. Proposed tetrahedral structure for the complex ion, [Cd(CP.HCl)2]2+

4. Conclusions

Four transition metal-chlorpromazine complexes have been successfully prepared and characterized based on their spectroscopic data. Square-pyramidal and tetrahedral geometries have been proposed for the new complexes. The future work would be on the determination of antioxidant and free radical scavenging activities of these complexes using standard assays.

ACKNOWLEDGEMENTS

The authors are grateful to the Western Illinois University Research Council and the National Cancer Institute-NIH (AREA grant # 1R15 CA115404-01) for support.