Oil-Soluble and Water-Soluble BTPhens and Their Europium

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Oil-Soluble and Water-Soluble BTPhens and their Europium Complexes in Octanol / Water Solutions: Interface Crossing Studied by MD and PMF Simulations. Gael Benay, and Georges Wipff J. Phys. Chem. B, Just Accepted Manuscript • Publication Date (Web): 07 Jan 2013 Downloaded from http://pubs.acs.org on January 12, 2013

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The Journal of Physical Chemistry

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Oil-Soluble and Water-Soluble BTPhens and their Europium Complexes in Octanol / Water Solutions: Interface Crossing Studied by MD and PMF Simulations. G. Benay and G. Wipff * Laboratoire MSM, UMR CNRS 7177, Institut de Chimie, 1, rue B. Pascal, 67 000 Strasbourg (France). [email protected]

Abstract. Bistriazinyl-phenantroline "BTPhen" ligands L display the remarkable feature to complex trivalent lanthanide and actinide ions, with a marked selectivity for the latter. We report on molecular dynamics studies of tetrasubstituted X4BTPhens: L4+ (X = +Et3NCH2-), L4- (X = -SO3Ph-) and L0 (X = CyMe4) and their complexes with EuIII in binary octanol / water solutions. Changes in free energies upon interface crossing are also calculated for typical solutes by potential of mean force PMF simulations. The ligands and their complexes partition, as expected, to either the aqueous or the oil phase, depending on the "solubilizing" group X. Furthermore, most of them are found to be surface active. The water soluble L4+ and L4- ligands and their (L)Eu(NO3)3 complexes adsorb at the aqueous side of the interface, more with L4- than with L4+. The oil soluble ligand L0 is not surface active in its endo-endo form, but adsorbs on the oil side of the interface in its most polar endo-exo form, as well as in its protonated L0H+ and complexed (L0)Eu(NO3)3 states. Furthermore, comparing PMFs of the EuIII complexes with and without nitric acid shows that acidifying the aqueous phase has different effects, depending on the ligands charge. In particular, acid promotes the EuIII extraction by L0 via the (L0)2Eu(NO3)2+ complex, as observed experimentally. Overall, the results point to the importance of interfacial adsorption for the liquid-liquid extraction of trivalent lanthanide and actinide cations by BTPhens and analogues.

Keywords: ion separation; liquid-liquid interfaces; molecular dynamics; PMF; f-ions.

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Introduction.

Ion separation by liquid-liquid extraction is the cornerstone of nuclear waste separation and partitioning.1-3 Generally, the source phase consists of aqueous solutions obtained by dissolution of irradiated fuel in nitric acid, while the receiving "oil" phase contains hydrophobic extractant molecules designed to selectively extract suitable ions. Typically, in the industrial PUREX process, tri-n-butylphosphate extracts uranium and plutonium that can be re-used as "MOX" fuel in reactors. The remaining waste solutions contain, among others, minor actinides (mainly AmIII and CmIII) that are the main contributors of the long term radiotoxicity.4 One possible strategy to solve this major environmental concern is to transmute them to shorter lived and /or less radiotoxic nuclei in fast neutron reactors, thus requiring prior separation from the LnIII lanthanides that have high neutron capture cross sections. Until recently, such separation appeared as quite impossible,5 due to close chemical similarities between trivalent actinides AnIII and lanthanides LnIII, but a breakthrough appeared with the synthesis of N-hetero-polycyclic ligands combining pyridinyl and 1,2,4-triazin-3-yl moieties:6 BTPs, BTBPs or the cis-locked BTPhens (Scheme 1) are so far the most efficient ligands for AmIII / EuIII separation,7-10 presumably because of specific orbital interactions between the metal and their soft N-donor sites.11-14 They generally bear alkyl substituents (e.g. lateral cyclic CyMe4 are more stable to radiolytic degradation than n-alkyl groups), and therefore partition in the oil phase where AnIII or LnIII is extracted. An alternative strategy for partitioning consists of using water-soluble derivatives of the ligands that selectively complex actinides in water, and to extract the remaining trivalent ions to the oil phase, using e.g. fatty diamides as transfer catalysts.15 The biphasic solutions involved in these processes are generally heterogeneous and complex, difficult to characterize by experiments only. On the other hand, molecular dynamics MD simulations on nano-sized biphasic systems, where noncovalent interactions are depicted by pairwise additive interactions of coulombic and van der Waals type (sometimes adding polarization) afford valuable microscopic views of selected extraction systems. Following studies on hydrophobic BTPs and BTBPs,16,17 we here report MD investigations on recently synthesized tetrasubstituted X4BTPhens (see Scheme 1) and their EuIII complexes in biphasic water-octanol solutions. The ligands are noted L4+ (X = +Et3NCH2), L4- (X = -SO3Ph) and L0 (X = CyMe4), respectively. L4+ and L4- are water-soluble, while L0 is oil-soluble. The complexes partition in the same phase as their ligands, and have typical 1:1 or 2:1 ligand:metal ratio, as evidenced by extraction and thermodynamic complexation data, NMR


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data in acetonitrile, X-Ray structures and spectroscopic data on BTPhen 18-21

analogues. 0

4-

2+

We thus consider the (L)Eu(NO3)3 and (L)2Eu(NO3)

9

or BTBP

complexes formed with

4+

L , L and L , respectively. We want to investigate how the ligands and the complexes distribute in the biphasic systems, with a particular focus on interfacial features. One key mechanistic issue in liquid-liquid extraction is to understand how the hard LnIII or AnIII, initially in water, can interact with hydrophobic ligands like L0, and what are the driving forces for partitioning to one phase or the other. Based on early MD simulations, we proposed that O-ligands like crown ethers,22 TBP,23 CMPO,24 calixarenes

25

that extract cations to

hydrophobic media are highly surface active, as are synergistic agents and specific anions, implying that ion capture and recognition occurs "right at the interface". When compared to these ligands, L0 and analogues are expected to be less surface active, and also more basic. They are generally less soluble in organic solvent like alkanes or their halide derivatives, but require more polar organic liquids (nitrobenzene, alcohols, ketones). Based on Quantum Mechanical (QM) calculations, we predicted that BTP, BTBP or BTPhen should be protonated at aqueous interfaces with nitric acid, raising the question of surface activity of their conjugated acids and related extraction mechanism.17,26 Nitric acid promotes the cation extraction by hydrophobic ligands like BTP, BTBP, BTPhen to the oil phase,6 and we want to test how this acid (a 5 M solution in our simulations) influences the distribution of neutral and charged ligands and their complexes near the interface. As oil phase we chose octanol where L0 and analogues are soluble and have been used to conduct complexation and extraction studies.9,27 On the methodological side, our approach is to first simulate the different biphasic systems by 10 ns of MD to test the partitioning of the different solutes, placed initially where they are supposed to sit, i.e. in water for L4+ and L4-, their counterions (NO3- and H3O+, respectively) and their complexes, and in octanol for the corresponding L0 ones. A second, more challenging approach is to calculate the free energy profiles for the migration of selected solutes (L0, L4- and L4+ ligands and their 1:1 complexes, the protonated L0H+ species, the 2:1 complex with L0, the Eu(NO3)3 salt, a single octanol molecule) across the liquid-liquid interface with "neutral" water and, in some cases, with acidic water. This is achieved by PMF (Potential of Mean Force) calculations, as reported for single ion transfer,28-30 Cs+ extraction by a calixarene 25 or the UO22+ extraction by tributylphosphate.31 Finally, in terms of coordination chemistry, it would be desirable to determine whether Xsubstituents like those studied are just innocent "solubilizing" groups, or also affect the ligand basicity and complexation strength and selectivity. For instance the acido-basic properties of



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carboxylic acids and amines in proteins are modulated by remote charged groups.32 As a first exploratory step, we also calculated by QM methods the basicity (at N-sites) of the L0, L4+ and L4- ligands and complexation energies with Eu(NO3)3 and Eu(H2O)43+ moieties in the gas phase and "in water".

Methods.

MD Simulations of biphasic solutions. Molecular dynamics simulations were performed with the AMBER10 software 33 with the following representation of the potential energy U: 6 12  qi q j  R*ij   R*ij   U = ∑ k l (l − l0 ) + ∑ k θ (θ − θ0 ) + ∑ ∑ Vn (1+ cos (n ϕ −γ ))+ ∑ −2 ε ij  + ε ij    Rij   Rij   bonds angles dihedrals n i< j  Rij       It accounts for the deformation of bonds, angles, dihedral angles, electrostatic and van der 2

2

Waals interactions. The solvents were represented explicitly at the molecular level, using the TIP3P model for water 34 and united atom models for octanol.35 The EuIII Lennard-Jones parameters were fitted on its free energy of hydration.36 Charges on X4-BTPhen were fitted on electrostatic potential obtained by QM calculations (DFT/ B3LYP/ 6-31G* level) on optimized pyridinyl and triazinyl derivatives and on X moieties, and further adapted to obtain the suitable total charge. This procedure turned out to give more satisfactory charges for buried atoms (e.g. Npyridine) than those obtained from calculations on the whole ligand.37 For the (X4BTPhen)Eu(NO3)3 and (X4BTPhen)2Eu(NO3)2+ complexes we used the charges obtained for the free ligands, Eu3+ and NO3- moieties. The complexes were simulated with weak harmonic constraints on Eu…N and Eu…ONO3 "bonds" (at ~2.8 and ~2.4 Å, respectively, with force constants of 20 kcal/mol/Å2) to avoid dissociation and to retain a bidentate coordination of nitrates during the dynamics.38 Unless otherwise specified, the conformation of the free and complexed ligands was endo-endo, as in the X-ray structure of the (CyMe4BTPhen)2Eu(NO3)2+ complex.9 Nitric acid was represented by a 25:75 mixture of HNO3 and H3O+ NO3- species in water, with the same parameters as in ref.39. Non-bonded coulombic interactions were calculated with the Ewald summation method (PME approximation, with the default AMBER10 parameters: grid spacing of ca. 1 Å, direct sum tolerance 10-5, i.e. Ewald parameter α = 0.23 Å-1 for a 12. 0 Å cut-off).40 The atom pairlists were updated every MD step. The biphasic solutions were simulated with 3D-periodic boundary conditions, thus as alternating slabs of water and octanol. The characteristics of the simulated systems are given in Tables 1 (MD simulations) and 2 (PMF simulations). Note that


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the biphasic solutions studied by MD generally contain three solutes per box (their concentration is ca. 0.02 mol/l in a given phase), while those studied by PMF simulations contain a single one. All systems were first relaxed by 3000 steps of energy minimization and by a MD simulation of 0.5 ns at 300 K and a constant pressure of 1 atm to adjust the densities. Subsequent dynamics were performed at constant volume for 10 ns. The temperature was maintained at ca. 300 K by coupling the solution to a thermal bath using the Berendsen algorithm 41 with a relaxation time of 1 ps. All O-H, C-H, N-H and H...H "bonds" were constrained with SHAKE (tolerance of 10-5 Å), using the Verlet leapfrog algorithm with a time step of 2 fs to integrate the equations of motion. Analysis of the trajectories. The solvent and solute densities were calculated as a function of the z-coordinate (perpendicular to the interface) in slices of ∆z = 0.2 Å width, and the position of the "interface" (z = 0; Gibbs dividing surface) was dynamically defined by the intersection of the “oil” and water density curves. The densities of solvents and solutes, averaged over the last 1 ns, were plotted as a function of their z-position. Interaction energies ∆Eint between the solute, water and octanol were calculated with a 12 Å cutoff and PME correction. Potential of Mean Force (PMF) calculations. We calculated the Helmholtz free energy profiles ∆A(z) for interface crossing by selected solutes S: the three types of ligands and their (L)Eu(NO3)3 complexes, the (L0)2Eu(NO3)2+ complex, neutralized by counterions when necessary (4 NO3- for L4+; 4H3O+ for L4-, Eu(NO3)52- for (L0)2Eu(NO3)2+). The PMF simulations started after a MD equilibration run (of 1 ns when water is "neutral" and of 5 to 10 ns when it is acidic) with the solute positioned "at the interface", equally shared by the two solvents. The position of S was characterized by the z-distance of its center-of-mass from "the interface" (defined by the intersection of the water and octanol density curves)42 where z = 0. The solute S was gradually moved from the interface (initial state: λ = 1) towards the water or the oil phase (final state: λ = 0) up to a z-distance of 20 Å, by steps ∆z = 0.5 Å, i.e. ∆λ = 0.025.

1

∆A =

∫0

∂U ∂λ

dλ

(2)

λ

The change in free energy at each step λ was calculated using the thermodynamic integration method (TI) based on equation (2).43At each λ step, we performed 0.5 ns of equilibration plus 1.0 ns of data collection and averaging, requiring a total simulated time of 60 ns per PMF.



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QM calculations. All structures were optimized at the DFT/B3LYP level of theory using the Gaussian09 software.44 The H, C, N, O atoms of the ligands were described by the 6-31G(d,p) basis set. As f-orbitals do not play an important role in metal-ligand bonding 45 the 46 core and 4f electrons of EuIII were described by quasi-relativistic effective core potentials (ECP) of the Stuttgart group.46 For the corresponding valence orbitals the affiliated (7s6p5d)/[5s4p3d] basis set was used 47 enhanced by an additional single f-function with an exponent of 0.591.48 QM calculations “in aqueous solution” were conducted in a polarizable continuum medium with a dielectric constant of 80, using the PCM implementation of Tomasi and coworkers (employing the united UFF radii scaled by 1.1 to define the van der Waals surface of the solute).49 This model does not account for specific (e.g. H-bonding) interactions with the solvent and cannot thus pretend to quantitatively predict basicities in solution, but can allow for consistent comparisons within a series as a function of the X substituents.

Results. We will first consider the oil-soluble ligand L0 in its free state (either neutral or protonated L0H+), and complexed as (L0)Eu(NO3)3 or (L0)2Eu(NO3)2+ species in biphasic octanol - water solutions. This will be followed by the case of water-soluble L4- and L4+ ligands and their 1:1 (L)Eu(NO3)3 and 2:1 (L)2Eu(NO3)2+ complexes. For each type of ligand, we first report the results of unconstrained MD simulations, followed by PMF results on selected systems. Note that some systems were investigated by one approach only to avoid prohibitive computational costs. In all systems, after 10 ns of dynamics, the two liquid phases are well separated and form "flat" interfaces on the average,50 in keeping with previous results on this system 51-53 and on related ones.54,55 At each interface octanol forms an irregular monolayer with O-H groups solvated by water. The octyl chains adopt more trans conformations than in the bulk liquid; they are more packed and form an "hydrophobic wall", possibly hindering transfer of ions, ligands and their complexes. The bulk octanol phase is not dry, but extracts some water (ca. 6 H2O when it contains neutral species like L0, and ca. 15 H2O when it contains polar solutes like L0H+ or (L0)Eu(NO3)3 complex, or when the aqueous phase is acidic). Furthermore, in acidic conditions, some nitric acid is extracted in its HNO3 neutral form to octanol, following experimental observations.56 In the following, we mostly focus on the partitioning of the solutes as a function of the charge of the ligand, the stoichiometry of its complex, and the presence of nitric acid. Regarding the


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EuIII coordination in (L)Eu(NO3)3 and (L)2Eu(NO3)2+ complexes with constrained bidentate nitrate(s), it involves additional H2O or NO3- species, depending on their local environment. I) Oil-soluble ligand L0 and its complexes at the octanol / water interface. Unconstrained MD dynamics. The L0 ligands and their complexes were simulated with three species per box initially distributed in the octanol phase at different positions, i.e. one at the center of the solvent slab, one closer to each interface. Because of their high mass and volumes and the solvent viscosity, the solutes diffused quite slowly during the dynamics. Diffusion coefficients D follow the order Dwater >> Doctanol > Dsolute (see results in Tables S1 and S2, including a comparison of different simulation protocoles). Cumulated positions over the last 5 ns (Figure S3) indicate that significant diffusion occurred, however. From the final snapshots (Figures 1 and S2) and density curves (Figure S3), it can be seen that the free L0 ligands have not reached the interface, but oscillate behind the octanol monolayer in bulk octanol. The protonated ligands L0H+ 57 and their NO3- counterions were likewise placed in octanol, but contacted with acidic water. Again, after 10 ns of dynamics, the three L0H+ molecules and their counterions remained in the organic phase, without crossing the interfacial octanol layer. Pursuing the dynamics for 5 ns at a higher temperature (350 K) to enhance the diffusion did not lead to interfacial activity, suggesting that there is no strong driving force for migration to the interface, and / or that this process involves some energy barrier (vide infra). The case of (L0)Eu(NO3)3 complexes differs since during the dynamics, one of them adsorbed at the interface, while two others remained in the oil phase, hinting for an equilibrium between these two positions. Likewise, the (L0)2Eu(NO3)2+ complex diffused from the bulk octanol to the interface. Interestingly, 1:1 and 2:1 complexes display different features at the interface. The former is neutral, but amphiphilic, i.e. points the Eu(NO3)3 moiety towards water and L0 towards octanol. The 2:1 complex is charged, but bulkier and its cation is more shielded from the solvent. As a result, it points more away from water. Also note the coordination of H2O molecule(s) to EuIII in the 1:1 and 2:1 complexes (1 and 2 H2O, respectively) at the interface.

Free energy results. We now turn to the calculated free energy profiles ∆A(z) for interface crossing by L0, L0H+, and the two types of complexes. Note that these have been obtained with one solute per box only (concentrations of ca. 0.01 mol / L in octanol) to avoid interferences with other solutes.



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Furthermore, because the complexes are known to be extracted from acidic solutions, we compare "neutral water" (no acid) with acidic water as source phase. The ∆A (z) curves are shown in Figure 2 together with snapshots "at the interface", while snapshots of end points in oil and in water are shown in Figures S4 to S6. During the equilibration step, L0 and its complexes remained on the oil side of the interface, at z ≈ -5 to -7 Å (I position). From there, every solute was stepwise moved 20 Å to the oil phase (z < 0) and 20 Å to the water phase (z > 0). The end points are noted W (bulk water) and O (oil phase). The resulting ∆A(z) curves display a flat minimum (I region) at the interface, and rise sharply (by ∆AIW ൎ 12 kcal/mol or more) towards water, which indicates that these solutes cannot partition to water. This feature also occurs for the L0H+ species that is quite hydrophobic, in spite of the +1 charge. Migration from the I position to the oil phase is a more facile process, with different characteristics depending on the solute. For L0, ∆A(z) first increases by ca. 3 kcal/mol (point B) and then decreases (point O when the ligand sits in "oil"). The ∆AIO energy difference is close to zero, indicating the lack of affinity of L0 for the interface, compared to the bulk octanol phase, explaining why L0 does not spontaneously adsorb at the interface during 10 ns of dynamics. At the I position, L0 turns its polar N-sites towards water, H-bonded to 2 - 3 H2O molecules (Figure 2), reminiscent of the H2O.L0 adduct observed in the solid state. 9,58 The loss of these water molecules and crossing of the octanol layer are likely the sources of the small energy barrier between the O and I positions.59 The case of L0H+, simulated with acidic water, somewhat differs, as its migration from I (oil side of the interface) to bulk octanol is an uphill process (∆AIO ≈ 4.5 kcal/mol), indicating that L0H+ prefers the interface over the bulk liquid and is thus surface active. Interestingly, at the interface, L0H+ adopts an "inverted" orientation, where the N-H+ bond points away from water (Figure 2), while the NO3- counterion sits in acidic water. The 1:1 and 2:1 complexes have been simulated with "neutral water" and with acidic water. For the 1:1 (L0)Eu(NO3)3 complex and neutral water, the free energy profile for migration from the interface (I position) to octanol (O) is not monotonous, but involves a small barrier (ca. 2 kcal/mol) to quit the interface and reach a minimum B where the complex sits just beyond the interfacial octanol layer (Figure S5). Upon further diffusion to the bulk oil, the energy increases by ca. 1 kcal/mol. Comparing energies at the I and O positions shows that the interface is not preferred over the bulk phase, but rather corresponds to a metastable or equally stable situation (∆AIO ≈ -1 kcal/mol). At the different positions, EuIII coordinates extra water ligands (1 H2O in octanol, 2 H2O in water and at the interface). When the aqueous


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phase gets acidified, the free energy profile from I to the oil phase is more flat and ∆AIO ≈ 0 kcal/mol, hinting for more facile transfer of the complex from the interface to the bulk octanol, or vice-versa. Furthermore, in the aqueous and organic phases, as well as at the interface, EuIII gets coordinated by two additional monodentate nitrates.60 For the 2:1 complex, the free energy profile displays a deep minimum (I) at the interface with neutral water. From there, no clear preference for either phase can be observed (∆AIO ≈ ∆A IW ≈ 8 kcal/mol), due to two antagonistic features: (L0)2Eu(NO3)2+ is charged (and attracted by water), but also bulky (hydrophobic). At the interface and in the two phases, EuIII coordinates an H2O molecule, sometimes exchanged for one NO3- in water. On the other hand, when the complex is moved to the oil phase, it is accompanied by only one NO3-, at ca. 8 - 10 Å from EuIII. This is not sufficient to achieve the neutrality required for the extraction when the aqueous phase is neutral. When the PMF simulation is carried out with acidic water, the ∆A(z) profile of the 2:1 complex is quite different: there is still a minimum (small, however) at the interface, but from there the complex clearly prefers the oil phase over the aqueous phase, and should thus be extracted. The main reason is the stabilization of the complex by counterions: at the interface and in both bulk phases, two additional monodentate nitrates coordinate to EuIII, affording a distorted (L0)2Eu(NO3)3 species. The latter is neutral, it does not coordinate extra water and is therefore more hydrophobic than (L0)2Eu(NO3)2+. As a result, ∆AIW is much higher with acidic water (> 20 kcal/mol) than with neutral water (ca. 8 kcal/mol). On the other hand, the neutralized complex migrates more easily from the interface to octanol when water is acidic (∆AIO ≈ 3 kcal/mol) than when it is neutral (∆AIO ≈ 8 - 10 kcal/mol). The significant differences between free energy profiles for neutral vs. acidic water for the 2:1 complex, and the differences between profiles for 2:1 and 1:1 complexes clearly demonstrate the crucial role of pH and counterions on the interfacial and extraction features of L0. II) Water-soluble ligands L4-, L4+ and their complexes at the octanol / water interface. Unconstrained MD dynamics. As for L0, we first present MD results obtained with three charged solutes per box, one initially positioned in bulk water and two closer to the interfaces. In principle, L4-, L4+ and their complexes are not involved in phase transfer processes and are thus expected to dilute in water. Our simulations show that this is not the case, as most of them prefer the interface, as seen from snapshots of unconstrained dynamics (Figures 3 and S8), average density curves



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and cumulated positions (Figure S9 - S10). All three L4- ligands rapidly adsorbed at the interfaces during the dynamics and stayed there, in an amphiphilic manner, perpendicular to the interface: the four sulfonate groups sit in water and form H-bonds with H2O molecules, while the hydrophobic phenantroline moiety is somewhat inserted into the first octanol monolayer. The H3O+ counterions are diluted in the bulk water at remote distances. The quaternary ammonium groups of L4+ have hydrophobic features and cannot form strong H-bonds with water. As a result, one of the three L4+ ligands remains near the center of the water slab while the two others approach near the interfaces, without penetrating the first octanol layer, however. These two "interfacial" L4+ ligands adopt different orientations, hinting for weak interactions with the interface: one of them (left interface in Figure 3) has two NEt3+ groups in contact with the octanol surface, while the two others point towards water, stabilized by two NO3- counterions. The other L4+ ligand (right hand side interface) is oriented more parallel to the interface, also fully surrounded by water. Let us now consider the 1:1 and 2:1 complexes. Note that their Eu atom captured ca. 2 H2O molecules during the dynamics, supporting their affinity for water, and the possible further dissociation of their nitrate ligands in water. The 1:1 complexes with one L4- or L4+ ligand also display a clear preference for the interface over the bulk water domain (Figure 3). All three (L4-)Eu(NO3)3 complexes adopt an amphiphilic orientation, as for the free L4- ligand. Analogous features appear for the (L4+)Eu(NO3)3 complexes, but these adopt less clearcut orientations near the interface, because their NEt3+ groups are less attracted by water than are the sulfonates. We now turn to the 2:1 complexes (L4±)2Eu(NO3)2+, simulated with one complex per box, neutralized by counterions to achieve electroneutrality (see Table 1). Increasing the number of complexed ligands from one to two clearly changes the interfacial behavior of the complex, due to antagonistic features: it becomes bulkier and hence more hydrophobic; on the other hand, its total charge increases in magnitude (from -4 to -6 for L4- ligands and from +4 to +10 for L4+ ligands), making it more hydrophilic. As a net result, the 2:1 complexes with either L4or L4+ have no marked affinity for the interface. During the dynamics, they mainly diffuse in the xy direction, displaying only transient contacts with the octanol surface (see Figure S10). The different distributions observed with L4- and L4+ and their complexes are fully consistent with the results of energy component analysis (Table S3): L4- and (L4-)Eu(NO3)3 anionic species are more attracted by water than are their cationic analogues (on the average, ∆Eint = 537 vs. -385 kcal/mol for the free ligands; ∆Eint = -640 vs. -540 kcal/mol for the complexes).


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On the other hand, the charged complex (L4±)2Eu(NO3)2+ is less well hydrated when its ligand is anionic than cationic (∆Eint = -1115 vs. -1460 kcal/mol). The water - soluble ligands and their 1:1 complexes also display significant attractions with octanol, and these are higher for L4- than L4+ free (-90 vs. -60 kcal/mol) or complexed (-115 vs. - 75 kcal/mol).

Free energy results. As for L0, we calculated the PMFs for the free L4- and L4+ species and their 1:1 complexes with the main aim to assess how deep is the free energy minimum "at the interface", and to compare the 4+ to the 4- charged ligands, using the same protocol as for the L0 species. Furthermore, the effect of nitric acid was investigated for the complexes. The ∆A(z) curves are presented in Figure 4 with typical snapshots of the I position. Snapshots at end points of the PMFs (in bulk water and bulk oil) are shown in Figure S11. The ∆A(z) curves confirm the reluctance of both charged ligands and of their complexes to move to octanol in either neutral or acidic conditions: at 20 Å from the I point, the energies have not been stabilized, but are at least 15 kcal/mol higher than in water. On the other hand, on the water side, ∆A(z) reaches a plateau in bulk water (point W), in keeping with the partitioning of the solutes in water. As stressed from the MD results reported above, the energy curves display a minimum on the water side of the interface (I position, with z ≈ 0 to 5 Å). Comparing the energy difference ∆AIW between the interface and bulk water confirms that L4- is more surface active than L4+ (∆AIW ≈ 6 and 1 kcal/mol, respectively). The same feature occurs for their 1:1 complexes (∆AIW ≈ 9 and 3 kcal/mol, respectively), as suggested by the MD results. When water gets acidified, the transfer of the complex with either L4- or L4+ ligands from water to octanol becomes clearly less unfavorable: the ∆AOW difference decreases from ca. 21 to -5 kcal/mol, and from ca. -14 to -3 kcal/mol, respectively. This feature stems from a better solvation of the complex in the octanol phase, due to H-bonds with HNO3 molecules, and from a "salting-out" effect on the water side. Furthermore, in acidic conditions (L4±)Eu(NO3)3 coordinates extra ligands. In the oil phase, the complex with either L4- or L4+ ligand coordinates one NO3- and one H2O. In water, (L4-)Eu(NO3)3 coordinates two extra H2O (one of them sometimes exchanging for 1 NO3-) while the positively charged (L4+)Eu(NO3)3 species attracts more anions and coordinates two monodentate NO3-. These results point to the effect of acid and surrounding medium on the speciation of the extracted metal, and on the change in interfacial properties.



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III) Interface crossing by the Eu(NO3)3 complex. We calculated the PMF for the preformed Eu(NO3)3 complex with constrained bidentate nitrates to investigate to which extent it can approach the interface, and the effect of acidity. The ∆A(z) curves are presented in Figure 5 with typical snapshots of the I position. Snapshots at end points O and W of the PMFs are shown in Figure S12. In neutral conditions, the complex takes up five additional H2O molecules along the PMF. The free energy profile from the aqueous phase to the I position (at ca. 5 Å from the interface) is quite flat. At this point, the first hydration shell of EuIII is in contact with the interface. When the complex is further pulled by ca. 15 Å towards the organic phase, the free energy increases up to 11 kcal / mol at position B where the complex is still connected to the aqueous phase by an elongated water cone. Then the cone disrupts, leaving the cation surrounded by 5 H2O molecules in its first shell, plus a few more remote ones, while the interface gets more "flat". The final ∆AIO energy difference drops to ca. 6 kcal/mol. In acidic conditions, Eu(NO3)3 captured 2 - 3 additional NO3- ligands (monodentate) plus 2 - 1 H2O molecules, formally forming an anionic complex. The latter approaches from bulk water to the interface with a small energy penalty (∆AWI ≈ 2 kcal/mol), while migration by further 15 Å is a more uphill energy process (∆AIO ≈ 12 kcal/mol). Note that at that stage, the complex is not really extracted, but is still connected with the aqueous phase via a cone of water molecules, presumably because charge neutrality in the organic phase has not been achieved. Thus, simulations without and with nitric acid confirm the reluctance of uncomplexed EuIII to cross the interface, even when its neutralizing counterions are coordinated. A fortiori, the "naked" cation cannot be transferred without complexing agent.

Discussion and conclusion

We report MD and PMF simulation results on a series of substituted BTPhen ligands and their complexes that are of utmost importance in the context of actinide / lanthanide partitioning by liquid-liquid extraction. The simulated systems are complex and require long simulations (multinanosecond timescale), preventing us using more sophisticated methods like CPMD 61,62

or inclusion of polarization in the force field.63 Sampling with "big" solutes in viscous

solvents like octanol is another crucial issue, as seen from the comparison of unconstrained


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MD versus PMF results on L0 and L0H+. Simulating in the NVT thermodynamic ensemble where temperature is regulated by the Berendsen thermostat procedure might also introduce artefactual oscillations or drifts during long MD simulations.64,65 To investigate this issue, we decided to simulate, as a test case, the biphasic system containing three (L0)Eu(NO3)3 complexes, in the NVE ensemble for 20 ns. As seen in Table S2, average temperatures of either the whole system or of its components (water, octanol, the solute) are quite the same in either NVT or NVE simulations, and the same at different intermediate times (4-5 ns, 9-10 ns, 19-20 ns). Likewise, the diffusion constants of the different components are similar, indicating that the protocole used for the simulations is satisfactory. Due to, among others, force field limitations (see e.g. a recent case study for the migration of a drug like molecule in a phospholipidic bilayer)66 and treatment of the boundaries, the results cannot pretend to be quantitative, but clearly point to the effect of the substituents on the partitioning of the ligands and their complexes: the neutral L0 species prefers the oil phase (octanol), while the charged L4- and L4+ species (with H3O+ and NO3- counterions, respectively) prefer the aqueous phase, as expected. Their 1:1 and 2:1 complexes partition as the corresponding ligands. The main focus of this paper is, however, on the interfacial behavior of the different species. Water - soluble ligands and their 1:1 complexes are surface active. The L4- and L4+ ligands that complex trivalent cations in water are found to be surface active, meaning that they should be more concentrated at the interface than in bulk water. Furthermore, there are clear differences between anionic and cationic substituents: the former (Ph-SO3-) are more hydrophilic and more surface active than the cationic ones (quaternary ammonium). Full characterization of the complexes in water (including possible coordination of counterions like nitrates and of solvent molecules), as a function of nitric acid and background electrolyte concentrations has not been achieved so far to our knowledge. At the interface, different complexation equilibria may occur compared to the bulk liquid, which deserves further investigations. The simulated 1:1 complexes with charged ligands, used for consistency throughout the study, are found to be surface active, as are L4- and L4+, also calling attention regarding the mechanism and kinetics of complexation by such water-soluble ligands, including their conformational properties.67 Is the oil - soluble ligand surface active? The neutral L0 type ligands are used mainly in liquid-liquid extraction processes, i.e. in biphasic conditions, requiring experimentally nitric acid to extract EuIII or AmIII ions from water to octanol. 9 Note that L0 is conformationally labile and, depending on the relative arrangements of the phenantroline and triazinyl rings, can be either endo-endo (as in the EuIII complex),9 exo-exo (as in the X-Ray structure of L0



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uncomplexed 9) or endo-exo. These forms have similar stabilities 68 and different dipole moments.69 The different conformers can thus be expected to be "attracted by the interface", i.e. point the polar N-atoms towards water. As shown in Figures 2 and S2, this is not the case for L0 endo-endo as such a positioning would immerse the hydrophobic CyMe4 groups in water, which corresponds to a repulsive situation. The resulting free energy at the interface (I position) is not deeper than in bulk octanol, supporting the lack of affinity of L0 endo-endo for the interface. Experimentally, interfacial tensions between aqueous phases of HNO3 1M and "oil" (oil = octanol, alkyl-cyclohexanones) decrease in the presence of L0 , which has been interpreted as a result of its surface activity. 9 This led us to reconsider the most polar form (endo-exo) of L0, and to recalculate the corresponding PMF for interface crossing. The resulting ∆A(z) profile (see Figure 6) looks in fact similar to the one of the endo-endo form, but displays now a small minimum at the interface, more stable than in "bulk" octanol (∆AIO = 3.5 kcal/mol), indicating that the surface activity of L0 depends on its conformation. Surface activity also depends on the nature and composition of the "oil phase". Octanol competes with L0 or analogues at the interface 59 and forms a "hydrophobic wall" between the bulk oil phase and the interface, possibly hindering exchanges between these two domains. Interestingly, phase transfer catalysts added to promote cation extraction, or other solvent molecules used in extraction experiments (e.g. alkyl-cyclohexanones)9 are also surface active and modify the composition of the interfacial layer and the surface activity of the ligands, possibly facilitating their migration from the bulk oil phase to the interface. Our PMF and MD results suggest that the surface activity observed for CyMe4BTPhen can stem from its protonated L0H+ form. At the interface, the latter is somewhat attracted by the hydrated NO3- counterion and interacts with water (by ca. - 90 kcal/mol) more than does L0 (ca. - 1 kcal/mol). There is no experimental determination of the L0 basicity at interfaces. Titration by 1H NMR in methanol upon addition of DCl yields a pKa of 3.1, close to the pKa of BTP in 76% methanol, lower than the pKa of phenantroline in water (4.9).9 Basicities are, generally speaking, highly dependent of the medium.70 As seen in our simulations, the environment of L0H+ at the interface is mainly hydrophobic, i.e. more gas phase-like than water-like, thereby increasing its proton affinity and supporting the above interpretation. Further support for the protonation of L0 by nitric acid stem from CP-MD simulations we performed on L0, contacted by either H3O+ NO3- or by HNO3 species in explicit water environment: in less that 1 ps, the N-pyridine atom captured the H(H3O+) or the H(HNO3) proton, to form the L0H+ species (see Figure S14).


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On the effect of nitric acid on EuIII extraction. When the aqueous phase gets acidified with nitric acid, the octanol phase gets more humid and extracts HNO3 species. In our simulations on nanosized solvent boxes, the two liquid phases remain well separated, but higher-sized heterogeneities like micelles or microemulsions can also form, facilitating the ion extraction.71 According to our PMF results, the acid has different effects on the solute partitioning, depending on the charge of the ligand and stoichiometry of the complex. For instance, for the L4- and L4+ containing complexes, the ∆AOW energy difference diminishes when acid is added. For the hydrophobic L0 and (L0)Eu(NO3)3 species, the reluctance to move to the water side of the interface increases with added acid, indicating that they would be more easily expelled out of the water phase. The most spectacular effect of the acid is seen on the PMF of the (L0)2Eu(NO3)2+ complex. Without acid, the latter is trapped at the interface, without clear preference for either water or octanol phase, due to antagonistic hydrophobic / hydrophilic features. In the oil phase, it co-extracts only one NO3- and is therefore not fully chargeneutralized. In acidic conditions, the complex is more reluctant to move towards water, it is no more trapped at the interface (small energy difference ∆AIO ≈ 3 kcal/mol), but can easily diffuse to bulk oil, and can be extracted. Acid thus increases the salting-out from water and, most importantly, affords full neutralization of the complex that becomes hydrophobic enough to be extracted. 72 Nitric acid also facilitates the approach of the EuIII ion to the interface, due to partial charge neutralization afforded by nitrates (see e.g. recent simulation study on uranyl nitrate 73). In the "pH neutral" bulk source phase, EuIII is mainly surrounded by water (ca. 8.5 H2O in the case of 3M Nd(NO3)3 solution).63 In highly acidic conditions, nitrates coordinate to the cation, rendering it less hydrophilic, and hence more surface active. Note that the interface has a lower dielectric constant than bulk water, and thus stabilizes tight ion pairs, thereby reducing the repulsions by the interface. This also facilitates interactions with the extractant molecule (neutral or protonated) at the interface.

Implications for the complexation and extraction mechanism by neutral ligands. Our simulations suggest that the surface activity of L0 depends on its conformation: the endo-endo form "preorganized" for complexation is not surface active, while the more polar endo-exo one is more active. In acidic conditions, it can be easily protonated, to form L0H+ endo-endo that also adsorbs at the interface, according to PMF results. The reluctance of L0 and L0H+ to move on the water side of the interface, and the reluctance of uncomplexed EuIII to partition in



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the octanol phase leads us to propose that the complexation reaction by such N-ligands has to occur "right at the interface", i.e. in a nanosized heterogeneous domain of the solution of particular composition and electrical properties, compared to the bulk domains. In the presence of acid, the concentration of protonated L0H+ at the interface becomes high enough to react with EuIII, a feature also facilitated by the high nitrate concentration from the dissociated acid.74 Nitrates attract L0H+ at the interface. They also promote the formation of europium nitrate anionic complexes suitable to react with L0H+ at the "interface" (possibly involving interfaces of micro-droplets when both phases are agitated and centrifugated).

On the effect of "solubilizing" X-substituents. The X-substituents affect not only the partitioning and interfacial activity of the ligands, but also possibly their basicity and binding strength, as seen for the para-pyridine R-substituted BTPs (R = H / Cl / OMe).75 Positively charged X may repulse the complexed Ln3+ cation or the N-H+ proton, while negatively charged groups should stabilize these species. Generally speaking, computing acido-basic properties in heterogeneous solutions is still a challenging task, requiring explicit modelling of the different proton states, of the solvent and environment. See e.g. CPMD,76,77 QM/MM 32 methods or methods based on empirical solvation models.78-80 This is beyond the scope of this paper but, as a first approach, we decided to calculate by QM methods the proton affinity of L0, L4+, L4- and analogues, as well as the complexation energies to form 1:1 complexes neutral (L)Eu(NO3)3 or charged (L)Eu(H2O)43+: H3O+

+ L →

LH+ + H2O

Eu(NO3)3

+L →

(L)Eu(NO3)3

Eu(H2O)43+

+L →

(L)Eu(H2O)4

Eprot 3+

Ec1 Ec2

The resulting energies Eprot, Ec1 and Ec2 in the gas phase and in PCM-water are reported in Table S7 with some comments. In the gas phase, the N(phenantroline) protonation energies Eprot and the complexation energies Ec2 follow the order L4- >> L4+ >> L0, due to field effects of the X substituents. Inductive + polarization effects can also be observed (e.g. in L0 for X = CyMe4 / H / Me / HSO3Ph; in L4+ for X =+Et3N / +Me3N). On the other hand, the Ec1 energies follow a different order (L0 > L4+ ≥ L4-) likely due to antagonistic interactions of X with the Eu3+ and NO3- moieties. In PCM-water, energies are mainly governed by the solvation of the most charged species, yielding different ordering of proton affinities and complexation energies. These features clearly hint for marked effects of X substituents on the "reactivity" of the ligand, but cannot be conclusive and call for other simulation and experimental studies.


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To summarize, our MD and PMF studies point to the crucial role of the substituents on the partitioning and interfacial behavior of BTPhen N-ligands and their complexes with EuIII, a mimics of trivalent actinides ions that are complexed and extracted with a high selectivity, compared to their LnIII analogues. Our results call for experimental investigations (e.g. surface spectroscopies coupled with surface tension measurements 81) of the distribution and orientations of the different oil-soluble and water-soluble partners at the interface, involving speciation of the complexes in this peculiar nano-domain of the solution. Regarding the effect of nitric acid, known to promote the extraction of trivalent ions by the ligands, we suggest several specific features involving the protonation of the ligands, and subsequent extraction mechanisms by hydrophobic ligands. Beyond water -oil interfaces, the "organization" of aqueous and oil phases in terms of aggregation, formation of microemulsions, of third phase also deserves further investigations.82,83 Acknowledgements. The authors are grateful to IDRIS, CINES, Université de Strasbourg and GNR PARIS for computer resources, and to E. Engler, A. Chaumont and R. Schurhammer for assistance. Support from the ACSEPT FP7 EEC collaborative project and stimulating discussions with the partners are greatly acknowledged.

Supporting Information: Tables with energy components analysis of the biphasic systems, diffusion coefficients, temperature tests and QM results. Figures including snapshots of the interfacial surface, snapshots and cumulated views along the different MD and PMF trajectories, density curves, PMF results for octanol across the interface, CPMD results for protonation of L0. This information is available free of charge via the Internet at http://pubs.acs.org.



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Tables and Figures. Table 1: Systems simulated for 10 ns by MD. Table 2: Systems studied by PMF simulations. Scheme 1. BTP, BTBP and simulated X4BTPhen ligands and their complexes. Figure 1: Oil soluble CyMe4BTPhen (L0) and its complexes at the octanol / water interface: snapshots after 10 ns of MD. See Figure S2 for snapshots and Figure S3 for cumulated views and average density curves. Figure 2: Interface crossing by L0, L0H+ and the L0 complexes in neutral and acidic conditions: free energy profiles and typical snapshots "at the interface". Snapshots at positions B, O and W are shown in Figures S4 to S6. Figure 3: Water soluble X4BTPhens (L4-, L4+) and their complexes at the octanol / water interface after 10 ns of MD. See also Figure S8 for snapshots at the interface and Figures S9 and S10 for cumulated views and average density curves. Figure 4: Interface crossing by L4- and L4+ ligands and their (L4±)Eu(NO3)3 complexes in neutral and acidic conditions: free energy profiles and typical snapshots "at the interface". Snapshots at endpoints O and W are shown in Figure S11. Figure 5: Interface crossing by Eu(NO3)3 in neutral and acidic conditions: free energy profiles (in kcal/mol) and typical snapshots "at the interface". Snapshots at positions O, W and B are shown in Figure S12. Figure 6: Interface crossing by L0 endo-exo: free energy profiles (in kcal/mol) and snapshot "at the interface". Snapshots at positions O and B are shown in Figure S13.

Supplementary Material Figure S1: Octanol / water solution containing three (L0)Eu(NO3)3 complexes: Snapshots of the interfacial surface at the end of the dynamics (right), 10 ps before the end (middle) and 100 ps before the end (left). Water on the top side (not shown) and octanol on the bottom side. Surface colored as a function of its z-position from red (water side) to blue (octanol side). Figure S2: Oil soluble CyMe4BTPhen (L0) and its complexes at the octanol / water interface after 10 ns of MD. Cumulated views and average density curves are given in Figure S3.


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Figure S3: Oil soluble X4TBPhen (L0) and its complexes at the octanol / water interface. Cumulated views over the last 5 ns (top) and density curves (bottom, average over the last ns) after 5 ns of MD. Figure S4: Interface crossing by L0 neutral and L0H+ protonated: snapshots at different positions along the PMF. Figure S5: Snapshots of the 1:1 complex with L0 at typical positions along the PMF. Figure S6: Snapshots of the 2:1 complex with L0 at positions O and W of the PMF Figure S7: PMF simulation for interface crossing by an octanol molecule, and typical snapshots at selected positions (512 octanol and 2109 H2O molecules in a box of 40x40x79+40) Å3. Figure S8: Water soluble L4-, L4+ ligands and their 1:1 complexes at the octanol / water interface after 10 ns of MD. See also Figures S9 and S10 for cumulated views and average density curves. Figure S9: Water soluble L4- and L4+ and their 1:1 complexes at the octanol / water interface. Cumulated views over the last 10 ns (top) and density curves (bottom, average over the last ns) after 10 ns of MD. Figure S10: 2:1 complexes of L4- and L4+ at the octanol / water interface: cumulated views over the last 10 ns (top) and density curves (bottom, average over the last ns). Figure S11: Snapshots of L4+ and L4- ligands and their 1:1 complexes at positions O and W of the PMF. Figure S12: Snapshots of Eu(NO3)3 at positions B, O and W of the PMF Figure S13: Octanol / Water interface crossing by L0 endo-exo: snapshots at positions B, O of the PMF Figure S14: CPMD simulations of proton transfer to cyMe4BTPhen in water: from H3O+ (first line) and from HNO3 (second line). Table S1: Typical diffusion coefficients D (in Å2 / ps; averaged over the last ns of dynamics) of water, octanol and the solutes in different biphasic systems. Table S2: Diffusion coefficients D (in Å2 / ps) for NVT vs NVE simulations along the dynamics of the octanol / water solution with three (L0)Eu(NO3)3 complexes. Table S3: Interaction energy of the ligands L and their complexes with the solvents (kcal



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/mol): averages and fluctuations (in parenthesis) during the last ns of dynamics (endo-endo conformation unless noted otherwise). Table S4: Testing the temperature from NVT vs NVE dynamics on the biphasic solution with three (L0)Eu(NO3)3 complexes. Top Table: Average temperature (Ttot) and temperature of the components (water, octanol, solute) averaged for 1 ns along the dynamics. Bottom graphs: Temperatures of water (blue), octanol (green) and total (red) as a function of time during 5 ns for NVT (left) and NVE (right) simulations of 20 ns. Table S5: Relative energies and dipole moment of neutral CyMe4BTPhen L0 with different conformations (B3LYP/ 6-31G(d,p) optimizations). Table S6: Relative energies of protonated CyMe4BTPhenH+ with endo-endo, endo-exo and exo-exo conformations (B3LYP/ 6-31G(d,p) optimizations). Table S7: Proton affinities and complexation energies of X4-BTPhens in the gas phase and in PCM-water calculated at the DFT/B3LYP/6-31G(d,p) level. The unsubstituted BTPhen (X= H) is the reference.


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(30) Schweighofer, K.; Benjamin, I.: J. Phys. Chem. A, 1999, 103, 10274-10279. (31) Jayasinghe, M.; Beck, T. L.: J. Phys. Chem. B, 2009, 113, 11662-11671. (32) Li, H.; Hains, A. W.; Everts, J. E.; Robertson, A. D.; Jensen, J. H.: J. Phys. Chem. B, 2002, 106, 3486-3494. (33) Case, D. A.; Darden, T. A.; Cheatham III, T. E.; Simmerling, C. L.; Wang, J.; Duke, R. E.; R. Luo; Crowley, M.; R.C.Walker; Zhang, W.; Merz, K. M.; B.Wang; Hayik, S.; Roitberg, A.; G. Seabra, I.; Kolossváry; K.F.Wong; Paesani, F.; Vanicek, J.; X.Wu; Brozell, S. R.; Steinbrecher, T.; H. Gohlke; Yang, L.; Tan, C.; Mongan, J.; Hornak, V.; Cui, G.; Mathews, D. H.; Seetin, M. G.; Sagui, C.; Babin, V.; Kollman, P. A.: AMBER10, University of California, San Francisco, 2008. (34) Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L.: J. Chem. Phys., 1983, 79, 926-936. (35) DeBolt, S. E.; Kollman, P. A.: J. Am. Chem. Soc., 1995, 117, 5316-5340. Note that in this model the 1-4 van der Waals interactions have to by divided by 8.0 (36) van Veggel, F. C. J. M.; Reinhoudt, D.: Chem. Eur. J., 1999, 5, 90-95. (37) For instance, the ESP q(H+) charge of BTPhenH+ calculated on the whole molecule is negative (-0.20 e). The q(H+) charge fitted on the pyridinyl moiety (+0.38 e) is more acceptable. (38) In the AMBER force field, Metal - Ligand "bonds" are depicted in a purely non-covalent manner, i.e. by van der Waals + coulombic attractions. Due to Ligand-to-Metal charge transfer, the latter may not be sufficient to compete with other EuIII interactions (with e.g. H2O species). Thus, harmonic restraints (force constant of 20 kcal/mol, and references distances taken from the optimized complex in solution) were imposed on Eu-N(Ligand) and EuO(NO3) distances to retain the coordination of the (Ligand)Eu(NO3)3 and (Ligand)2Eu(NO3)2+ complexes during the dynamics. (39) Schurhammer, R.; Wipff, G. In Separations and Processes Using Supercritical Carbon Dioxide; Gopalan, A. S., Wai, C., Jacobs, H., Eds.; ACS: Washington, DC, 2003; Vol. 860, Chap. 15, pp 223-244. (40) Darden, T. A.; York, D. M.; Pedersen, L. G.: J. Chem. Phys., 1993, 98, 10089. (41) Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; DiNola, A.: J. Chem. Phys., 1984, 81, 3684-3690. (42) When the solute is moved away from the interface, the precise location of the interface along the Z-axis may be somewhat shifted. We thus recalculated the crossing of the solvents density curves at every step of the PMF, and used this updated reference for the results presented here. (43) Kollman, P.: Chem. Rev., 1993, 93, 2395-2417. (44) Gaussian 09, R. B., M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. . Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2010. (45) Maron, L.; Eisenstein, O.: J. Phys. Chem. A, 2000, 104, 7140-7143. (46) Dolg, M.; Stoll, H.; Savin, A.; Preuss, H.: Theoret. Chim. Acta, 1989, 75, 173-194.


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(47) Dunning, T. H.; Hay, P. J. In Methods of Electronic Structure Theory. Modern Theoretical Chemistry 3.; Schaefer III, H. F., Ed.; Plenum Press: New York, 1977; Vol. 3, pp 1-28. (48) Ehlers, A. W.; Böhme, M.; Dapprich, S.; Gobbi, A.; Höllwarth, A.; Jonas, V.; Köhler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G.: Chem. Phys. Lett., 1993, 208, 111-114. (49) Tomasi, J.; Mennucci, B.; Cammi, R.: Chem. Rev., 2005, 105, 2999-3093. (50) In fact, the octanol / water interface, flat on the average, is rough and dynamics. See e.g. snapshots at different times in Figure S1. The interface roughness, defined by the ratio of the "real" interfacial area, and the xy section is 2.2 ± 0.08, on the average. During 10 ns of dynamics, octanol molecules diffuse parallel and perpendicular to the interface, often exchanging between the interface and the bulk regions. As a result, the diffusion coefficients of octanol are similar in both regions (see Table S2). The lifetime of octanol at the interface is ca. 2.1 ns (average for all molecules than sit for at least 0.1 ns between -11 and +5 Å from the interface). (51) Napoleon, R. L.; Moore, P. B.: J. Phys. Chem. B, 2006, 110, 3666-3673. (52) Chevrot, G.; Schurhammer, R.; Wipff, G.: Phys. Chem. Chem. Phys., 2007, 9, 1991 2003. (53) Benjamin, I.: Chem. Phys. Lett., 2004, 393, 453-456. (54) Benjamin, I.: Acc. Chem. Res., 1995, 28, 233-239 and references cited therein. (55) Volkov, A. G.; Deamer, D. W.; Tanelian, D. L.; Markin, V. S. Liquid Interfaces in Chemistry and Biology; John Wiley & Sons, Inc.: New York, 1998. (56) Geist, A.: Solv. Extract. Ion Exch., 2010, 28, 596-607. (57) The L0H+ ligand was simulated in the endo-endo form (same form as in the EuIII complex) with the proton on the N-phenantroline, as suggested by Lewis et al. 9. The stability of this form is also supported by QM calculations we performed on its endo-endo, endo-exo and exo-exo forms in the gas phase and in PCM-water (see Table S6): the endo-endo and endo-exo protonated forms have similar stabilities in the gas phase and in water, and the proton prefers the N-phenantroline over N-triazine. (58) Note however that in the solid state structure, the conformation of L0 is not endo-endo (as in the EuIII complex) but exo-exo. (59) Octanol itself displays a free energy profile similar to that of L0 (see Figure S7). Octanol is a surface active molecule, but the energy difference between the bulk and interfacial positions is close to zero (∆AIO = 0.7 kcal/mol). These positions are separated by a barrier of 1.2 kcal/mol. Note the satisfactory agreement for our calculated free energy difference between the water and octanol phases (∆AwO = 6.2 kcal/mol) and the experimental value of ca. 5.8 kcal/mol (see J. Sangster: "Octanol - Water Partition Coefficients", Wiley series in Solution Chemistry, 1997, Vol. 2, p. 7). (60) If the constraints on the nitrate ligands are released, they become monodentate and an extra H2O coordinates to Eu,yielding a total coordination number of 10 after 1 ns (61) Pollet, R.; Nair, N. N.; Marx, D.: Inorg.Chem., 2011, 50, 4791–4797. (62) Terrier, C.; Vitorge, P.; Gaigeot, M.-P.; Spezia, R.; Vuilleumier, R.: J. Chem. Phys. , 2010, 133, 044509. (63) Duvail, M.; Ruas, A.; Venault, L.; Moisy, P.; Guilbaud, P.: Inorg. Chem., 2010, 49, 519530. (64) Chiu, S.-W.; Clark, M.; Subramaniam, S.; Jakobsson, E.: J. Comput. Chem., 2000, 21, 121–131. (65) Harvey, S. C.; Tan, R. K.-Z.; Cheatham III, T. E.: J. Comput. Chem 1998, 19, 726-740. (66) Paloncýová, M.; Berka, K.; Otyepka, M.: J. Chem. Theory Comput., 2012, 8, 1200-1211. (67) According to AMBER optimizations, the relative energies of the endo-endo, endo-exo and exo-exo forms of L4- are 0, 24 and 38 kcal/mole, respectively. For L4+ they are 0, 5, 10



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kcal/mol, respectively. (68) According to QM optimizations at the DFT/B3LYP/6-31g(d,p) level, the relative energies of the endo-endo, exo-exo and endo-exo forms of L0 are 0.0, -3.5 and -3.2 kcal/mole, respectively in the gas phase and 0.0, 0.4, -0.6 kcal/mol, respectively in PCM-water. (69) According to QM calculations, the dipole moments of L0 endo-endo, exo-exo and endoexo are: µ = 2.1, 1.8 and 4.7 Debye respectively in the gas phase, and µ = 3.9 , 2.5 , 6.3 Debye respectively in PCM-water where L0 is polarized by the surrounding medium. With our AMBER force field, µ = 3.4 , 1.0 and 4.4 Debye, respectively, indicating that the dipoles are rather well represented. (70) For instance, aniline is more basic than NH3 in the gas phase, but is less basic than NH3 in water, due to lower solvation of anilinium, compared to NH4+ cation in water. See R.W. Taft, "Protonic Acidities and Basicities in the Gas Phase and in Solution : Substituent and Solvent Effects", in Physical Organic Chemistry 1983, 14, 247-350. (71) Osseo-Asare, K.: Separation Sci. Technol., 1988, 23, 1269-1284. (72) In our simulations, the extracted complex involves one bidentate plus two monodentate nitrates, but alternative patterns cannot be ruled out, involving e.g. uncoordinated nitrates at short distances (as we observe without acid), H-bonded to co-extracted HNO3 or H2O species. (73) Ye, X.; Smith, R. B.; Cui, S.; deAlmeida, V.; Khomami, B.: Solv. Extract. Ion Exch., 2010, 28, 1-18. (74) Interestingly, when compared to the CyMe4BTBP analogue whose bipyridine unit is trans , the cis-preorganized CyMe4BTPhen does not require phase transfer catalysts to extract EuIII or AmIII. We suggest that this is due to the higher basicity (and complexing ability) of the latter, as supported by QM results.17 It becomes thus also more surface active. (75) Trumm, S.; Wipff, G.; Geist, A.; Panak, P. J.; Fanghänel, T.: Radiochim. Acta, 2011, 99, 13-16. (76) Simon, C.; Ciccotti, G.; Klein, M. L.: ChemPhysChem 2007, 8, 2072 – 2076. (77) Sulpizi, M.; Sprik, M.: J. Phys. Condens. Matter, 2010, 22, 284116. (78) Ho, J.; Coote, M. L.: J. Chem. Theory Comput., 2009, 5, 295–306. (79) Eckert, F.; Diedenhofen, M.; Klamt, A.: Molecular Physics: An International Journal at the Interface Between Chemistry and Physics, 2009, 108, 229-241. (80) Simonson, T.; Carlsson, J.; Case, D. A.: J. Am. Chem. Soc. , 2004, 126, 4167-4180. (81) Martin-Gassin, G.; Gassin, P. M.; Couston, L.; Diat, O.; Benichou, E.; Brevet, P. F.: Phys. Chem. Chem. Phys., 2011, 13, 19580–19586. (82) Meridiano, Y.; Berthon, L.; Crozes, X.; Sorel, C.; Dannus, P.; Antonio, M. R.; Chiarizia, R.; Zemb, T.: Solv. Extract. Ion Exch., 2009, 27, 607-637. (83) Chiarizia, R.; Briand, A.: Solv. Extract. Ion Ech., 2007, 25, 351-371.


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Table 1: Systems simulated for 10 ns by MD. Solute Noctanol Nwater 4-

+

3 [L , 4H3O ]

Box size (Å)

867

6869

59x59x(60+59)

871

6786

59x59x(60+59)

3 [(L )Eu(NO3)3, 4H3O ]

873

6853

59x59x(60+59)

3 [L4+, 4NO3-]

871

6796

59x59x(59+60)

869

6840

59x59x(60+59)

867

6794

60x60x(58+59)

820

7075

4-

+

+

-

3 [L H , 4H3O , NO3 ] 4-

4+

+

+

-

3 [L H , 5NO3 ] 4+

-

3 [(L )Eu(NO3)3, 4NO3 ] 0

3 [L ] 0

+

-

3 [L H , NO3 ]

59x59x(58+60) a

827

185 “Acid”

821

7061

59x59x(58+60)

1 [(L )2Eu(NO3) , 8H3O ] and 1 Eu(NO3)52- in water

500

3912

49x49x(49+50)

1 [(L4+)2Eu(NO3) 2+, 8NO3-] and 1 Eu(NO3)52- in water

510

3950

50x50x(50+49)

3 [(L0)Eu(NO3)3] 4-

2+

+

59x59x(58+64)

1 [(L0)2Eu(NO3)2+] in octanol 475 4101 49x49x(49+50) and 1 Eu(NO3)52- in water a : "Acid":= 3 NO3-, 3H3O+, 1 HNO3 and 30 H2O (5M nitric acid represented by a 25:75 mixture of neutral and dissociated species) Table 2: Systems studied by PMF simulations. Solute a) Noctanol Nwater Box size (Å)

(ns) b

L4-, 4H3O+ 4+

L , 4NO3

-

488

4039

49x49x(49+50)

1

492

4059

49x49x(50+49)

1

4-

+

488

4066 H2O

49x49x(50+49)

1

4+

-

493

4055 H2O

49x49x(51+48)

1

493

4060 H2O

(L )Eu(NO3)3, 4H3O

(L )Eu(NO3)3, 4NO3 0

(L )Eu(NO3)3

49x49x(49+50)

1

493

105 "Acid"

c)

49x49x(49+50)

10

489

105 "Acid"c)

49x49x(49+50)

10

(L )Eu(NO3)3

492

106 "Acid"

c)

50x50x(49+50)

10

L0 endo-endo

496

4077 H2O

49x49x(49+50)

1

L endo-exo

499

4072 H2O

50x50x(50+49)

5

L0H+

493

105 "Acid"c)

50x50x(49+50)

5

(L )2Eu(NO3)

475

4101 H2O

49x49x(49+50)

10

Eu(NO3)3

256

2124 H2O

40x40x(40+40)

1

4-

+

(L )Eu(NO3)3, 4H3O

(L4+)Eu(NO3)3, 4NO30

0

0

2+

c)

Eu(NO3)3 257 53 "Acid" 40x40x(39+40) 1 a) Concentration is 0.01 M in water. b) Equilibration time before starting the PMF. c) "Acid":= 3 NO3-, 3H3O+, 1 HNO3 and 30 H2O



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Scheme 1. BTP, BTBP and simulated X4BTPhen ligands and their complexes. R X X

N N

R N

N N

N

X

N

N

X

X

N N N

X

N

N

N

N

N

N N

X

N N N

N N

X

N X X

X

N Eu

N

N

N N N O– +O– N N O 3

X X

N

N X

N N N

N N

X

X X

Eu

1:1 complex (L)Eu(NO3)3

X

X4BTPhen L4- and L4+

CyMe4BTPhen L0

N

X

BTBP

N N N

N N

X

BTP

N

N

N

O– +O– N O

2

Eu(NO3)52-

2:1 complex (L)2Eu(NO3)


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3 (L0)Eu(NO3)3

3

L0H+ Nitric Acid

3 L0

Figure 1: Oil soluble CyMe4BTPhen (L0) and its complexes at the octanol / water interface after 10 ns of MD. See Figure S2 for snapshots and Figure S3 for cumulated views and average density curves.

(L0)2Eu(NO3)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60




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(L0)2Eu(NO3)1

(L0)Eu(NO3)3 Acidic Water

(L0)Eu(NO3)3

L0H+

L0

Figure 2: Interface crossing by L0, L0H+ and the L0 complexes in neutral and acidic conditions: free energy profiles and typical snapshots at the interface. Snapshots at positions B, O and W are shown in Figures S4 to S6. Snapshot at I position ∆Α (kcal/mol) as a function of Z (Å)

(L0)2Eu(NO3)1 Acidic Water

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Figure 3: Water soluble X4BTPhens (L4-, L4+) and their complexes at the octanol / water interface after 10 ns of MD. See also Figure S8 for snapshots at the interface and Figures S9 and S10 for cumulated views and average density curves. Free Ligands 3 L4-, 12 H3O+

1:1 Complexes

3 (L4-)Eu(NO3)3

2:1 Complex (L4-)2Eu(NO3)2+

Free Ligands 3 L4+, 12 NO3-

1:1 Complexes

2:1 Complex


3 (L4+)Eu(NO3)3

(L4+)2Eu(NO3)2+



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(L4-)Eu(NO3)3 Acidic water

(L4+)Eu(NO3)3

(L4-)Eu(NO3)3

L4+

L4-

Figure 4: Interface crossing by L4- and L4+ ligands and their (L)Eu(NO3)3 complexes in neutral and acidic conditions: free energy profiles and typical snapshots "at the interface". Snapshots at endpoints O and W are shown in Figure S11. Snapshot at I position ∆Α (kcal/mol) as a function of Z (Å)

(L4+)Eu(NO3)3 Acidic water

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Neutral water

Figure 5: Interface crossing by the Eu(NO3)3 complex in neutral and acidic conditions: free energy profiles (in kcal/mol) and typical snapshots "at the interface". Snapshots at positions O, W and B are shown in Figure S12.

Acidic water

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 6: Interface crossing by L0 endo-exo: free energy profiles (in kcal/mol) and snapshot "at the interface" (I position). Snapshots at positions O and B are shown in Figure S13.




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Table of Contents (TOC) Image Oil-Soluble and Water-Soluble BTPhens and their Europium Complexes in Octanol / Water Solutions: Interface Crossing Studied by MD and PMF Simulations. By G. Benay and G. Wipff *


Oil-Soluble and Water-Soluble BTPhens and Their Europium

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