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Effects of Water Molecules on Metal Complexes of Hydroxyoxime and Carboxylic Acid Extractants

Water molecules around the cobalt(II) (Co) and manganese(II) (Mn) complexes of the hydroxyoxime extractant, LIX63 and/or of the carboxylic acid extractant, Versatic acid 10 (VA10), in cyclohexane solvent were investigated using molecular dynamics calculations with simulated annealing. For the complexes of VA10, water molecules were coordinated to the metal ions, and VA10 molecules were found around the complexes. For the complexes of LIX63, a few water molecules were located at ~ 0.4 nm from the metal ions, in addition to the LIX63 molecules were also coordinated to the metal ions. Our trajectory analysis indicates that the water molecules at ~ 0.4 nm are hydrogen-bonded to LIX63 or other water molecules, suggesting that the hydrogen bonding contributes to the stabilization of the metal complex.


Introduction
In solvent extraction processes for separation and purification of critical metal ions in aqueous solution, it has been reported that water molecules play an important role in the stabilization of the metal complexes formed in the organic solvent. The stability of the metal-extractant complex in the organic solvent is theoretically known to be related to the extraction efficiency, and the stabilization mechanism has been researched experimentally and theoretically. Consequently, it is useful to specify the position of one water molecule around the metal ion in order to understand the extraction mechanism at an atomic level.
Although synergistic extraction using the multiple extractants has been researched and the mechanisms have been elucidated in some cases [1][2][3][4][5], several aspects remain undefined at an atomic level.
It has been reported experimentally that the efficiency curve, representing the pH-dependence, of the extraction of cobalt(II) by the hydroxyoxime extractant, LIX63 used in combination with the carboxylic acid extractant, Versatic acid 10 (VA10), is shifted by two pH units compared to LIX63 alone [6], called synergistic effect. However, the 3-dimensional structure of the metal complexes formed by these extractants is unclear.
In this paper, the distribution of molecules/ions around the cobalt(II) (Co) or manganese(II) (Mn) ions was investigated by using molecular dynamics (MD) calculations with simulated annealing (SA). All calculations were carried out in cyclohexane (CHX) as diluent. LIX63 and VA10 ( Figure 1) were selected as the hydroxyoxime and carboxylic acid extractants, as experimental data for these were available [6]. We performed the calculations with six systems (Co-LIX63, Mn-LIX63, Co-VA10, Mn-VA10, Co-(LIX63+VA10) and Mn-(LIX63+VA10)). In addition to the extractants, all systems contained ten water molecules to examine their distribution around the metal ion. The SA trajectories were analyzed and revealed that water molecules not coordinated to the metal ions contribute to the stability of the metal complexes.

Methods
MD simulations were performed with the GROMACS software package [7,8] using the general AMBER Force Field [9] (for CHX, LIX63 and VA10), TIP3P water model [10] (for H 2 O) and parameters developed by Li and Merz [11,12] (for Co 2+ , Mn 2+ and Cl -) and by Sagnella and Voth [13] (for H 3 O + ). The atomic charges of CHX, LIX63 and VA10 were calculated using the AM1-BCC method [14,15]. The initial model systems were constructed by using one Co 2+ or Mn 2+ ion and 10 water molecules with 10 LIX63 and/or 10 VA10 molecules. These systems were embedded in rectangular boxes solvated with 508 CHX molecules in a periodic boundary condition, and H 3 O + and Clwere added to neutralize the system. The box sizes were set to be 4.6 nm x 4.6 nm x 4.6 nm.
To avoid the coordination of Clto the metal ions in the Co-and Mn-VA10 systems, the distances between metal ions and Clwere restrained. Our pre-calculations with the Co-and Mn-VA10 systems containing free Cl -, which were 500-ns MD calculations and SA calculations, showed that free Cl -'s were coordinated to the metal ions immediately and not exchanged with other molecules. The structures of the metal complexes were very similar with that in aqueous solution including no extractant. Thus, to focus on the effect of water molecules on the complexes, we used the distance restraints. For applying the restraints, the restraint potential form V(r) is where r is the distance between the metal ion and the chloride ion, r 0 is set to be 1.5 nm, and k is the force constant, 500 kJ/mol/nm 2 .
Initial structures for the SA calculations were prepared as follows; after minimization, gradual heating to 300 K in 500 ps and equilibration at 300 K for 10 ns were carried out. The pressure of the systems was maintained at 1 bar by Parrinello-Rahman approach [16,17] and the temperature was controlled by the velocity-rescaling thermostat [18]. The final structures in the simulations were used for the next SA calculations.
The structure sampling was carried out with 8 cycles of the SA calculations. Each cycle consisted of five steps; (i) equilibration at 300 K for 250 ps, (ii) heating from 300 to 800 K for 500 ps, (iii) equilibration at 800 K for 500 ps, (iv) cooling from 800 to 300 K for 500 ps and (v) equilibration at 300 K for 250 ps.
We analyzed the SA trajectories in step (i) and (v) during the last 5 cycles. The volume of the systems was fixed, and the temperature was controlled by the velocity-rescaling thermostat [18].
In all MD simulations, the particle-mesh Ewald algorithm [19] was used for long-range electrostatic interactions, and other short-ranged nonbonding interactions were calculated using a cut-off of 1.2 nm. A time step was set to be 1.0 fs and conformations were saved every 1 ps.

Results and Discussion
The structures of the Co or Mn complexes containing LIX63 and/or VA10 were estimated using the SA trajectories during last 5 cycles (see above). During the SA calculations, the molecules coordinated to the metal ions were exchanged frequently according to the system temperature. Because these observed structures might be in metastable states, not stable states, we performed six 500-ns MD calculations starting from the configurations chosen from each SA trajectory. These MD results showed that the structures of the metal complexes did not changed and were in stable states. Consequently, the snapshots of the SA trajectories were analyzed to compare the structures of the metal complexes.

Complexes coordinated with LIX63
Our analysis of the SA trajectories shows that there are several coordination structures of the Co-LIX63 complexes. The appearance frequency of the Co-LIX63 complexes is classified in Table 1 according to the number of coordinated molecules and the coordination number. The coordination number is defined as the number of the atoms in the sphere of 0.30 nm radius centered on the metal ion, and the appearance frequency, f ij , was calculated from: where n ij is the number of the MD snapshots with the number of the coordinated molecules i and the coordination number j, and N total is the total number of the snapshots. The 3-dimensional descriptions of the structure of the Co-LIX63 complexes are listed in Table 1. Despite water molecules being present in the system, the Co-LIX63 complex with the highest appearance frequency, that is, the most stable complex, contained only LIX63 molecules. b) The square pyramidal geometry is distorted.
-27 - molecule is removed, the Co complexes become the 5-coordinate. The angular distribution of ligands of these structures is drawn in Figure 2 (a). The peak at 180° is broad and shifted, and the peak at 90° is broad.
This suggests that these structures have distorted 5-coordinate geometries. The space where one H 2 O molecule was coordinated is occupied with the hydrocarbon groups of LIX63 ligand. Visual inspection of some of these 5-coordinated structures of the Co complexes suggests that they are distorted square pyramidal or approximately trigonal bipyramidal. On the other hand, the 5-coordinated structures in Figure   2 (b) and (c) have more nearly regular square pyramidal. The distortion of the 5-cordinated structures is mainly caused by the steric hindrance of the LIX63 hydrocarbon groups, but also might be a consequence of the inadequacy of the force field parameters used in the calculations. The contribution of these H 2 O molecules around Co 2+ to the stabilization of the Co complexes will be discussed later.
The structures of the Mn-LIX63 complexes are different from those of their Co analogues. Table 1 and Figure 2 (e-i) show that all of the Mn-LIX63 complexes are 6-coordinated and pseudo-octahedral. All contained the coordinated water molecule(s). This suggests that water molecules are important in contributing to their stabilization.
To examine the role of the water molecules, we compared results with those from our previous study where MD simulations with no water molecules were performed [20]. This comparison shows that the appearance frequency of 6-coordinated structures of the Mn complexes is increased by the presence of water molecules, indicating that the interaction of water molecules with Mn 2+ and LIX63 enhances stability.
However, though the frequency of the 5-coordinated structures in the Co systems with H 2 O is found to be greater, the most prevalent Co complex was one of no H 2 O ligands (see also Table 1). This suggests that the water molecules not coordinated to metal ions can also contribute to the stabilization of the complexes. In     the CHX-excluded volume, that is, the effective size of the metal complex depends on the metal ion. We define the effective radius of the metal complex (r eff , see below) as the position of the first peak or the shoulder of g(r) with CHX.

Complexes coordinated with VA10
The appearance frequency distributions of the Co-and Mn-VA10 complexes are listed in Table 2. All these complexes have 6-coordinated pseudo-octahedral structures. In these systems, H 2 O molecules are mainly coordinated to the metal ions and the number of coordinated VA10 molecules is 2 or less.   should be noted that, in the VA10-only system, r eff for Mn 2+ is shorter than for Co 2+ , but in the LIX63-only system, r eff for Co 2+ is shorter than for Mn 2+ . This relationship is consistent with the efficiency tendency reported by experiments [6].

Complexes coordinated with LIX63 and VA10
The appearance frequencies of the Co-(LIX63+VA10) complex are listed in Table 3. LIX63 molecules were mainly coordinated to Co 2+ . It is noteworthy that all of the complexes contain no VA10 molecules coordinated to Co 2+ . This suggests that VA10's role is in controlling the environment around the Co complexes (see below).  b) The square pyramidal geometry is distorted.
To examine the 3-dimensional structures of the Co-(LIX63+VA10) complexes, the angular distribution of the ligands was calculated. Figure 7 (a-c) indicates that the 6-coordinated structures are present in the stable complexes. However, Figure 7 (d) indicates that the 5-coordinated complexes can have square pyramidal geometries and the widths of the peaks at 90° and 180° suggests that these complexes are distorted.
The Mn-(LIX63+VA10) complexes have the two structures shown in Table 3. They are pseudooctahedral (see also Figure 7 (e) and (f)) and contain 3 LIX63 molecules coordinated to Mn 2+ . In CHX solvent (see Figure 9). The hydrogen bonding and the hydrophobic interactions of VA10 in the systems with LIX63 and VA10 are likely to make the complexes more stable. Although it is difficult to estimate the hydrophobic interaction energy, the qualitative order: coordination energy > hydrogen bond energy > hydrophobic interaction energy usually applies and consequently, in these systems, hydrogen bonding is likely to enhance extraction efficiency more than the hydrophobic interaction.  additional LIX63 molecules are found in the range with r > 1.5 nm in the LIX63-only system. In spite of this difference in the mode of stabilization, the mixture of LIX63 and VA10 has a higher appearance frequency of the 6-coordinated complexes (see Table 3).
The structures of the Co-and Mn-(LIX63+VA10) complexes calculated in our SA simulations are not in agreement with the Ni complex formed by 5-hydroxy-4-octanone oxime (as an analogue of LIX63) and iso-propionic acid (as an analogue of VA10) [21]. This inconsistency might be due to the different length of hydrocarbon groups of these ligands. The smaller steric hindrance in the model complexes may cause the complexes to be stable. As mentioned above, the nature of the hydrocarbon groups and water molecules located at ~ 0.4 nm has an effect on the stabilization of the metal complex in the organic solvent.
Our observation shows the importance of the water molecules located at ~ 0.4 nm.
The effective radius, r eff , of the Co and Mn complexes in the systems with LIX63 and VA10 are 0.53 nm and 0.55 nm, respectively. This difference is consistent with that of the efficiency for extraction of the two metal ions using either single or mixed extractants and indicates that r eff values are useful in predicting relative extraction efficiencies and metal ion selectivities, i.e. screening combinations of potential extractants. In general, to do this, lots of knowledge about the chemistry of metal ions and the propeties of extractants is needed and the appropriate experimenal measurements sometime are time-consuming. On the other hand, selection using r eff values could prove to be more efficient and effective.
In our simulations, only phenomena in the water-immiscible solvent have been considered. As solvent extraction involves two immiscible phases and it is also necessary to consider the effects of the interface between the phases. Such effects are being examined and will be reported elsewhere. For simplicity, hydrogen atoms in LIX63 and VA10 are not shown.

Conclusion
We have investigated the structures of Co(II) or Mn(II) complexes with LIX63 and/or VA10 extractants and the positions of uncoordinated water molecules using SA calculations. The Co and Mn complexes with LIX63 or VA10 contain a few water molecules located at ~0.4 nm from the metal ions.
These water molecules are hydrogen-bonded to the LIX63/VA10 and water molecules coordinated to the metal ions. These hydrogen bonds might contribute to the stability of the complexes. In solvent extraction of Co and Mn using mixed LIX63 and VA10 extractants, the stabilization of the metal complexes is enhanced by the exclusion of the water molecules and the replacement of H 2 O with VA10.
The effective radius, r eff , calculated from the first peak or shoulder of g(r) of C atoms of CHX correlates with experimentally observed extraction efficiency. The dependence of r eff on the nature of metal ions and the extractants shows that coordination energies and hydrophobic interactions play important roles in determining the extraction efficiency. Consequently, we could use r eff to predict relative extraction efficiencies and metal ion selectivities.