Synthesis, Metal Ion Complexation and Computational Studies of Thio Oxocrown Ethers

The synthesis of some thio-oxocrown ether ligands, B1 (1,4-dithio-12-crown-4), B2 (1,7-dithio-12-crown-4), B3 (1,7-dithio-15-Crown-5), B4 (1,7-dithio-18-crown-6), B5 (1,10-dithio-18-crown-6), B6 (1,10-dithio-21-crown-7), under mild conditions, were reported. The ligands were characterized by FT-IR, 1H NMR and GC-MS spectroscopy. The formation of 1:1 ligand complexes with a variety of metal salts (Ag+, Ca+2, K+, Na+, Mg+2, Zn+2 and Fe+2) were investigated by a conductometric method in a 1:1 dioxane–water system at 25 °C, and the complexation constants (Ke = (ΛMAm -Λ) / ((Λ-ΛMaLbAm) [L]) and free energy (∆Go= - RT lnKe) values are calculated. Details of the specific molecular interactions between the ligands and metals were proposed. We also performed DFT calculations to explain their geometrical properties, charges and frontier molecular orbitals.


Introduction
Synthetic macrocycles, in particular crown ethers, have been known for over three quarters of a century, although a real spate of publications in this area was observed in the late 1960s [1,2]. In that period, thousands of macrocyclic compounds were reported, and since then their number has increased markedly from year to year. Crown ethers contains "hard" ether-oxygen-bridges and show a binding preference toward "hard" metals (such as alkali and alkaline earth metal cation). The replacement of oxygen-bridge with "soft" sulfide or amine linkages can shift their preference towards "soft" heavy OPEN ACCESS metal cations [3]. Thus, selectivity can be tuned by combining different hard/soft donor atoms in one ring system. In this regard oxo-thiocrown ethers are prepared and used as potential heavy-metal receptors. In this work, oxo-thiocrown ethers having different ring size or arrangement have been prepared and their complexation properties have been investigated with various metal cations by conductometry [4][5][6][7].
More recently, interest in differences in the properties of metal complexes caused by replacement of one or more thioether sulfurs with amine nitrogen atoms has been apparent in the literature [8,9]. In spite of this and the obvious connection between crown ethers and thiocrown ethers, until quite recently [10,11], less effort has been devoted to a comparison of O,S donor complexes with complexes of these other ligand systems. As part of our continuing interest in the properties of both acyclic and cyclic ligands that have thioether and other donors [12,13], we have examined the properties of some metal complexes of ligand L and the results are reported herein for the purpose of comparison with those from homothioether and mixed S,N donor macrocyclic ligand complexes [14].
Binary mixed aqueous solvents are frequently employed in broad areas of chemistry. Their applicability ranges from synthetic and mechanistic studies in organic chemistry to biophysical chemistry, with emphasis on molecular interactions in biologically significant structures. Stability constants of crown compound-action complexes are determined by various methods, such as potentiometry (with ion selective electrodes), polarography, voltammetry, spectrophotometry, NMR, calorimetry and solubility. The ability of macrocyclic polyethers (crown ethers) to form stable complexes with cations, mainly with alkali and alkaline earth cations, has spurred interest in these compounds 15-17. Recently published studies include conductometric measurement of some electrolytes in non-aqueous solvents (tetrahydrofuran 18, tetrahydropyran 18, acetonitrile 19,20 and methanol 20) in the presence of crown-ethers. Studies carried out in solutions of alkali metal salts and crown-ethers in acetonitrile and methanol showed decreases in conductivities of the solutions.
The experimental findings were also supported by theoretical computations. The gas phase molecular mechanical and quantum chemical calculations of B1, B2, B3, B4, B5, and B6 were performed at B3LYP/6-31G(d) level with the help of the Gaussian03 program.
For example, if we have prepared dithio-18-crown-6 using both ways, the product obtained from ditosylate is less than the product made from the dichloride because, the tosylate is a group that can be separated in S N 2 mechanism under normal conditions but it is too hard to remove it from complex donor crown ethers. Especially, that's hard to purify the molecules which have -S center oxygen, so their yields are lower.
Various methods to calculate stability constants from measurements of properties involving intrinsic factors, such as molar conductivity etc. have been described in the literature 21-23. When an oxo-thiocrown ether ligand (L) forms a complex (M a L b m+ ) with a cation (M m+ ), the equilibrium equation can be written as: where M m+ , L, and  are respectively the cation, ligand and fraction of free cations. Thus the equilibrium constants K e of different ratios of complex formation were calculated using the following equations (2)- (13): The observed conductivity, , is given by: The molar conductivities are: As a result of Eq. (12), Eq. (2) can be transformed into: In the present work, considerable solvent effects of water were displayed for B1 (1,4-dithio-12crown-4), B2 (1,7-dithio-12-crown-4), B3 (1,7-dithio-15-crown-5), B4 (1,7-dithio-18-crown-6), B5 (1,10-dithio-18-crown-6), B6 (1,10-dithio-21-crown-7), owing to differences in K e depending on the solvent composition. The selectivity for a given salt is a factor not only of the crown ether, but of the solvent as well [21,24]. These various selectivities depend on the crown ether interactions with the cations governed by charge density.
The complexation of the synthesized products with Na + , K + , Ca 2+ , Zn 2+ , Mg 2+ , Ag + and Fe 2+ was studied by conductometry in 50% dioxane-water at 25 °C and original results were obtained. The complexation selectivity of B1 with Na + , K + , Ca 2+ , Zn 2+ , Mg 2+ , Ag + and Fe 2+ ions, were observed to be as follows: Na + > Fe 2+ > Mg 2+ > Ca 2+ > Ag + > K + > Zn 2+ . The best complexation of with B1 with Na + can be explained by the possibility of having sandwich molecules with more than one ion because its ring cavity is bigger.
B6, gives the order Mg 2+ > Na + > Ca 2+ > K + > Zn 2+ >Fe 2+ > Ag + . The best complexing with B6 is Mg 2+ . All oxo-thio crown ethers B1-B6 have systematic variations in the ring size of the crown ether ring from [12]crown-4 to [15]crown-5 to [18]crown-6 to [21]crown-7, respectively. Results of our alkali metal complexation study using oxo-thio crown ether derivatives are presented in Table 1. One of the most impressive results of this study is the dithio-12-crown-4 and dithio-18-crown-6 derivatives' complexing ability in dioxane-water system. Some specific results were obtained by exchanging of oxygen and sulphur in the crown-ring. For example, for Ag + the best are B1, B3, B2 and then, B6 is lesser. Mg ++ has the highest complexing ability with B6, and it complexes with B3 and B5. This is caused by the conformational difference between the oxygens and sulphurs in the structure. The ligands which best complex with the metals were determined in this sequence: for NaCI and KCl B1 is the best, for ZnCl 2 B3, for MgCl 2 B6, for FeSO 4 and CaCl 2 B2.

Computational Results
The difficulty of the theoretical calculations can be attributed to the complication of supramolecular structures. Various quantum-chemical and force-field computations of crown ethers and of their metal complexes have been reported recently [24,[26][27][28], even on the ab initio level [29,30] and the density functional level of theory (DFT) [31][32][33]. The structures of molecules play an especially significant role in determining their chemical properties. Therefore, we study the most stable geometries of the six crown ethers. In order to obtain the preferred conformers, the simulated anneling technique was employed initially [34]. The simulation protocol involving a heating time of 0.1 ps, followed by a 1 ps simulation at 3,000 K and cooling to 298 K within 50 ps was applied at AM1 self-consistent field molecular orbital level [35]. Quantum-mechanical calculations were carried out on initially geometry optimized structures at the DFT level using the Gaussian03 suite of programs [36]. The DFT methods are effective for the theoretical studies of supramolecular structures [37][38][39]. The B3LYP, a version of the DFT method, which uses Becke's three-parameter functional (B3) [40] and includes a mixture of HF and DFT exchange terms associated with the gradient corrected correlation functional of Lee, Yang, and Parr (LYP) [41]. Hence, B3LYP method is used in this article to perform quantum chemical calculations. The optimized structures for the crown ethers studied herein in their gorund states were obtained and are shown in Table 2. The dihedral angles were also calculated to analyze the planarity of molecules. The ring-contracted crown ether B5 has the biggest dihedral angle, Ø SOOS = 42.51 and indicates the most distorted structures for series of compounds. The results indicate that when a methylene between two adjacent oxygen atoms of a crown ether is reduced, the rigidity of the crown ring is increased and the structure of the crown ether shows a drastic change in the atoms' disorder. However, compared to the conventional crown ethers B2 and B3, the ring-contracted crown ethers all depict a relatively good oxygen planarity because the crown ether rings became more soft and relaxed for the changing of the methylene-chain length between sulfur and oxygen atoms. The calculated real vibrational frequencies of B1, B2, B3, B4, B5, and B6 at B3LYP/6-31G(d) level show that the molecules are located as a minimum on potential energy surfaces.
The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of molecules are quite important to define its reactivity. Fukui et al. were the first to recognize this. E HOMO is often called with the electron donating ability of the molecules [42]. E HOMO depicts that the molecular ability in donating electrons to appropriate acceptor molecules with low energy, empty molecular orbital. On the contrary. E LUMO indicates the ability of the molecule to accept electrons. The lower value of E LUMO , indicates that the molecule would accept electrons. Hence, concerning the value of the energy gap, E(E LUMO -E HOMO ), higher values of E will provide lower reactivity to a molecule. Lower values of E will indicate the higher reactivity of the molecules, because the energy to remove an electron from the HOMO to the LOMO orbital will be low [43][44][45][46]. Frontier molecular orbital diagrams and energies of B1, B2, B3, B4, B5, and B6, such as E LUMO , E HOMO , and E (in eV) estimated by the B3LYP/6-31G(d) levels are represented in Table 2.  Table 2, the majority of HOMO and LUMO are found on the donor atoms in the crown ether ring, suggesting the high electron-donating ability of heteroatoms. Table 3 shows the atomic charges from natural population analyses (NPA) for B1, B2, B3, B4, B5, and B6. The calculated charges on the sulfur atoms are considerable more positive than that on oxygen atoms. Results primarily indicate the role of delocalized oxygen charges on the torsional barrier of gauche oxyethylene units of crown ethers which could optimize charge densities and therefore the preferred conformations. This also influenced the polarization balances of the rest of atoms in a macromolecule governing the power of macrocycle-cation interactions.

General
The starting materials triethyleneglycoldiol, diethyleneglycoldiol, triethyleneglycol dichloride, diethyleneglycol dichloride, triethyleneglycol ditosylate diethyleneglycol ditosylate, ethylene ditosylate, Cs 2 CO 3 and thiourea were purchased from Aldrich or Merck. IR spectra were recorded on a Perkin Elmer BX 2 FTIR spectrophotometer using KBr pellets. 1 H-NMR spectra were recorded on a Varian 400 MHz spectrometer in CDCl 3 and chemical shifts are reported relative to Me 4 Si used as an internal standard. Mass spectra were obtained using a Shimadzu GS-MS-QP2010 spectrometer. Melting points were measured on an Elektotermal 9200 apparatus.

The Synthesis of Dithiols
Triethyleneglycoldithiol from triethylene glycol (Method A): triethyleneglycol (24 mL, 0.18 mol) and thiourea (30 g, 0.39 mol) were heated in HCl (150 mL) for 40 hours under reflux. Then, the reaction mixture was left to cool to room temperature. A 3.3 M aqueous KOH (300 mL) was added carefully to the reaction mixture. The solution was left to cool to room temperature, and then organic products were extracted into ether (2 × 150 mL). Combined extracts were dried over MgSO 4 , the solids were filtered and the solvent was evaporated under reduced pressure to give a crude material as liquid. Upon distillation (5 mm Hg, 140 °C) the title product (12.02 g, 36%) was obtained as a yellow liquid. 1

The Synthesis of Oxo-thiocrown Ethers
General procedure: ditosylate/dichloride was added to a suspension of dithiol (1.1 equiv.) and Cs 2 CO 3 (5.0 equiv.) in acetonitrile (250 mL). The mixture was then heated under reflux for 24 h under a nitrogen atmosphere. The reaction was left to cool to room temperature and then the precipitates were filtered. The solvent was evaporated under reduced pressure to give a crude material as solid.
Distilled water (100 mL) was added and organics were extracted into benzene-chloroform (10:1 v/v). Combined extracts were dried over MgSO4 and then evaporated under reduced pressure. Purification by column chromatography (benzene/ethyl acetate; 1:10 v/v) afforded the title compounds.

Conductimetric Method
Merck grade alkali halides (NaCl and KCl) were recrystallized three times from a conductivimetric grade water-ethanol mixture and Merck grade AgNO 3 , CaCl 2 , MgCI 2 , ZnCl 2 and FeSO 4 ) were used directly. All of the salts were heated below their decomposition temperature at reduced pressure to remove traces of water in the crystal structure. Bi-distilled water was redistilled from alkaline permanganate. All solutions were prepared in dry glassware and transferred into the pre-dried conductivity cell.
All conductances were measured at 25  0.05 °C. The measuring equipment consisted of a glass vessel (Ingold type) with an external jacket connected to a thermostatted water-bath (25  0.05 °C) and a conductivity cell (Cole Parmer 19050-66) with a conductometer (Suntex Model SC-170).
The cell constant was determined to be 0.769 cm −1 at 25  0.05 °C by measuring the conductivity of aqueous KCl solutions of different concentrations 21,25. A value of the molar conductivity of the pure metal ion solution ( MA ) was obtained at the appropriate electrolyte concentration before adding any ligand.

Conclusions
In conclusion, various macrocyclic hosts with diverse affinity towards the metal ions and other funtions have been readily synthesized by changing the combinations of the oxygen and sulfur atoms forming the ring framework. The synthesized thiocrown ethers exhibited remarkably high binding constants in metal ion transport experiments [21,24,26].
The synthesized macrocyclic ethers exhibit different binding ability orders towards the examined metal ions. Although the effect of various synthesized thiocrown ethers on the transport ability of the studied metal cations was not investigated systematically, preliminary results show that thiocrown ethers may possess an advantage over crown ethers containing only oxygen atoms in the cyclic framework for metal binding, because the introduction of a sulfur atom into a crown ring gives rise to a favorable entropic change upon complexation with the metal ions. The results strongly suggested that the binding results from the synergistic coordination with polarization balance of the oxygen and sulfur atoms to the metal ions.
As a result, we have demonstrated that a complementary theoretical and experimental approach can provide important information on oxo-thiacrown ethers complexation with various metal ions (Ag + , Ca +2 , K + , Na + , Mg +2 , Zn +2 and Fe +2 ), essential elements in a wide variety of processes in biological systems. The position of sulfur atom in the crown ether ring plays an important role in determining the ethers' properties, as it can not only change the cavity size, but may also cause a disorder of the atom arrangement. Less-symmetrical crown ethers show remarkable recognition and binding properties towards specific metal cations compared to the highly-symmetrical crown ethers (Tables 1, 2, and 3). It is believed that both of them will be widely applied in the future.