Di- and Trivalent Metal-Ion Solution Studies with the Phosphinate

Aug 15, 2017 - (1-3) This approach is particularly true in the context of metal-based imaging agents—for magnetic resonance imaging (MRI) or positro...
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Di- and Trivalent Metal-Ion Solution Studies with the PhosphinateContaining Heterocycle DEDA-(PO) David M. Weekes, Maria de Guadalupe Jaraquemada-Peláez, Thomas I. Kostelnik, Brian O. Patrick, and Chris Orvig* Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada S Supporting Information *

ABSTRACT: A 7-membered triprotic heterocycle, DEDA(PO), was synthesized, characterized, and tested for its solution properties with three trivalent lanthanides (La3+, Gd3+, and Lu3+) and three biologically relevant divalent metal ions (Ca2+, Zn2+, and Cu2+). The ligand synthesis has been reported once before; however, the characterization results were previously misinterpreted to correspond to a larger, 14-membered heterocycle, TETA-(PO)2. This manuscript serves to correct the original paper. Potentiometric titrations were carried out with each of the metal ions, and the thermodynamic stability values in terms of log β and log KML were calculated showing a 1:1 metal-to-ligand ratio preference for the divalent metal ions and a 1:2 ratio for the lanthanides. The stability of the 1:2 complexes decreased across the lanthanide series, presumed to be a steric effect. Further resolution to the potentiometry results was given via pH-dependent NMR spectrometry (with La3+) and pH-dependent UV−vis spectroscopy (with Cu2+), and the pM values were calculated for all metal ions. The solid-state structure of the 1:1 Cu2+-DEDA-(PO) complex was further characterized by X-ray crystallography.

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INTRODUCTION The rational design and efficient synthesis of bifunctional chelators to match specific metal ions is a fundamental component of medicinal inorganic chemistry.1−3 This approach is particularly true in the context of metal-based imaging agentsfor magnetic resonance imaging (MRI) or positron emission tomography (PET), for examplewherein a great deal of research has been dedicated to seeking out ligands that enhance the specificity toward an in vivo target, thereby optimizing the diagnostic power of a given metal−ligand complex.3−6 A major challenge associated with these systems is preventing metal-ion transchelation by endogenous binding groups, which can lead to nonspecific distribution throughout the body or deposition in nontarget tissues. In response to this challenge, ligands are often designed around macrocyclic moieties that generally offer high complex thermodynamic stability. Some of the best-known examples include the Ncarboxylated polyazamacrocycles NOTA, DOTA, and TETA (Chart 1), which have been studied with a wide range of metal ions including copper(II), manganese(II), gallium(III), and europium(III).7−9 In a continued effort to develop new ligands with improved stability and specificity, we aimed to synthesize the diphosphinate-containing tetraazamacrocycle TETA-(PO)2 (Chart 2, left), which had been reported once previously by our research group in 2002.10 Therein, we sought to enhance the chelation properties with trivalent lanthanides (Ln3+), which have a number of therapeutic and diagnostic applications,11,12 a theme that aligned with our own ongoing research goals.13 To our surprise, when the outlined synthetic procedure was repeated, © 2017 American Chemical Society

Chart 1. Three N-Carboxylated Polyazamacrocycles That Have Been Studied for Their Chelation Properties with a Range of Metal Ions in the Quest for Thermodynamically Stable Medicinal Imaging Agents

Chart 2. Structures of the Previously Reported Macrocycle TETA-(PO)2 (Left) and the Actual Product DEDA-(PO) (Right)

the isolated product was not TETA-(PO)2 but rather a smaller 7membered diazaheterocycle, herein referred to as DEDA-(PO) Received: May 3, 2017 Published: August 15, 2017 10155

DOI: 10.1021/acs.inorgchem.7b01117 Inorg. Chem. 2017, 56, 10155−10161

Article

Inorganic Chemistry

Finally, crystals suitable for solid-state X-ray analysis were obtained that showed H3DEDA-(PO)·3H2O as the double zwitterion (Figure 1 and Table S1). Overall, the characterization

(Chart 2, right). Characterization data in terms of NMR spectroscopy and elemental analysis were consistent with both species; however, crucial evidence in the form of a solid-state crystal structure and high-resolution mass spectrometry (reported herein) proved unambiguously that the only obtained product was the smaller of the two heterocycles. To the best of our knowledge DEDA-(PO) has not been reported previously, and our original report10 of TETA-(PO)2 was incorrect. In an effort to set the record straight, we present herein the chelation properties of DEDA-(PO) with the same trivalent lanthanide ions that were investigated in the original paper (La3+, Gd3+, and Lu3+),10 as studied by potentiometric titrations. Because of the size difference between the original and actual ligands, we performed titrations in both 1:1 and 1:2 metal-toligand (M/L) ratios and investigated the dynamic processes for lanthanum complex formation in solution using variable-pH 1H and 31P NMR spectrometry. The trends in the results were compared to the tetravalent ligand N,N′-ethylenediaminediacetic acid (EDDA), the solution chemistry of which with Ln3+ was well-defined thanks to the work of Thompson, Martell, and others.14−17 Biologically relevant divalent metal ions (Ca2+, Zn2+, and Cu2+) were similarly studied by potentiometry in 1:1 and 1:2 M/L ratios, and a comparison of their pM values (which take into account the metal−ligand association and ligand basicity under physiologically relevant conditions) with those of Ln3+ and EDDA is included. Additional qualitative titration data for the Cu2+-DEDA-(PO) system was obtained by UV−vis spectrophotometry, and an X-ray crystal structure of the 1:1 complex K[Cu(DEDA-(PO))]·H2O was obtained and is described.

Figure 1. ORTEP diagram of H3DEDA-(PO)·3H2O. Associated crystallographic data are presented in Table S1.

data unequivocally indicate the formation of DEDA-(PO) rather than TETA-(PO)2. Furthermore, there is a strong entropic argument against the formation of the 14-membered macrocycle, in which eight separate components must come together to form the product in a single reaction mixture (compared to four components for the 7-membered heterocycle). Despite our best efforts, we were unable to identify the reaction conditions under which TETA-(PO)2 could be generated. Stepwise protonation constants for DEDA-(PO) were determined by potentiometric titrations (Table 1). These studies

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Table 1. Stepwise Protonation Constants for DEDA-(PO) As Determined by Potentiometric Titrations ([L] = 1.0 × 10−3 M at 25 °C and I = 0.16 M NaCl) Using the Software HyperQuad201323 and EDDA from Reference 14 ([L] = 1.0 × 10−3 M at 30 °C and I = 0.10 M KNO3)

RESULTS AND DISCUSSION Synthesis and Characterization of DEDA-(PO). The product was generated in a single step with a moderate yield via a 1:1 Mannich-type addition of EDDA with phosphinic acid in the presence of excess formaldehyde and under harsh acidic conditions (refluxing 6 M HCl; Scheme 1). This chemistry was

species log Ka1 log Ka2 log Ka3 log Ka4 log Ka5

Scheme 1. Synthetic Route to H3DEDA-(PO) as the HCl Salt a

DEDA-(PO)

EDDAb

8.15(1) 4.50(1) 2.00(3) 1.61(8) NDa

9.46 6.42 NDa NDa

2−

HL H2L− H3L H4L+ H5L2+

ND = not determined. bFrom ref 14.

were performed at a ligand concentration [L] = 1.0 × 10−3 M at 25 °C and I = 0.16 M (NaCl). From the fully deprotonated species [DEDA-(PO)]3−, there are five positions available for protonation, with the first two assigned to quaternization of the tertiary nitrogen groups (log Ka1 = 8.15; log Ka2 = 4.50). These results are compared to the known values for the amine groups of EDDA (log Ka1 = 9.46; log Ka2 = 6.42),14 with the difference in the basicity being due to the electron-withdrawing nature of the phosphinate group in DEDA-(PO). For the phosphinate and carboxylate functionalities, protonation constants of less than 2 are expected,3 and as such, only two of these values were determined by potentiometric titrations (log Ka3 = 2.00; log Ka4 = 1.61). Solution Studies with DEDA-(PO) and Trivalent Lanthanides. Potentiometric titrations in 1:1 and 1:2 M/L ratios in the pH 2−11 range with DEDA-(PO) were used to determine the stability constants (log β and log K) of the trivalent ions La3+, Gd3+, and Lu3+ (25 °C and I = 0.16 M NaCl). These values serve to correct those originally put forward in ref 10 and are compared to literature values for EDDA (Table 2). The

first pioneered by Smith18 and further developed by Varga19 and is now a well-established protocol for the catalyst-free formation of (aminomethyl)phosphinates and (aminomethyl)phosphonates.20−22 High dilution is preferred in order to favor cyclization over polymerization, with the product precipitating from the crude reaction mixture as the HCl salt. Characterization data by 1H, 13C{1H}, and 31P{1H} NMR were consistent with the 7-membered heterocycle as well as with its previously reported “double” TETA-(PO)2.10 Elemental analyses were also consistent with one another because of equivalent elemental stoichiometries for both the smaller and larger heterocycles (as the single and double HCl salts, respectively). Mass spectrometry data (TOF-ES, negative-ion mode) revealed a single dominant peak at m/z 265.0, consistent with [M − H]− for H3DEDA-(PO). This peak had originally been attributed to [M − 2H]2− for H6TETA-(PO)2; however, the distinctive lack of a mass signal at m/z + 0.5 suggested that the monoisotopic peak was solely due to a singly charged species. 10156

DOI: 10.1021/acs.inorgchem.7b01117 Inorg. Chem. 2017, 56, 10155−10161

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1:2 complexes with smaller metal ions. Indeed, it has been noted previously that ligands with six coordinating groups or more do not form 1:2 complexes with trivalent lanthanides.16,20 Because DEDA-(PO) is pentavalent, its trend in the stability of 1:1 complexes likely lies somewhere between the two scenarios. In addition to potentiometric titrations, pH-dependent 1H NMR (Figure 3) and 31P NMR (Figure S4) spectra were collected for the La3+-DEDA-(PO) system in both 1:1 and 1:2 M/L stoichiometric ratios. Qualitatively, the results are in agreement with the speciation plots presented in Figure S1, which show in the 1:1 system the formation of La(DEDA-(PO)) almost exclusively at approximately pH 4 (labeled A). Above pH 8, the 1:2 species La(DEDA-(PO))23− (labeled B) and a precipitate begin to form, indicative of the equilibrium with La(OH)3 above pH 10. In the 1:2 system, a broadening of the signals in the 1H NMR spectrum between pH 3 and 5 is indicative of a mixture of free ligand and 1:1 and 1:2 species in solution. These signals become well resolved in the 1:2 species (B) above approximately pH 6, which remains the dominant metal−ligand species in solution up to pH 11. Solution Studies with DEDA-(PO) and Divalent Metal Ions. Complex formation of Cu2+, Zn2+, and Ca2+ with DEDA(PO) was studied by potentiometric titrations in a 1:1 and 1:2 M/L ratio (25 °C and I = 0.16 M NaCl). The resulting stability constants are presented in Table 3 and serve to correct those originally calculated in ref 10 with the misidentified ligand. The results are compared to literature values for EDDA and demonstrate that DEDA-(PO) follows the expected trend in stability across the series (Ca2+ < Zn2+ < Cu2+).14,16,24 Complex formation with Cu2+ was further examined qualitatively by pHdependent UV−vis spectrophotometry (Figure 4), and the results fully support the corresponding speciation diagram (Figure 5). The 1:1 complex [Cu(DEDA-(PO))OH2]− begins to form above approximately pH 1.5, as indicated by an increase in the absorbance of the d−d absorption band to λmax = 670 nm in the UV−vis spectra (Figure 4 a). This species is stable in a range of approximately pH 3−9, above which a transformation occurs due to the loss of a proton from a coordinated water molecule, generating the species [Cu(DEDA)-(PO))OH]2−. This deprotonation is marked by the isosbestic point at λ = 769 nm and the shift of the absorption band to lower energies (Figure 4 b). Above pH 11.3, precipitation was observed, indicating the formation of insoluble copper hydroxide species. From the titrations performed thus far (and from the literature)14−17 pM values at pH 7.4 were calculated for EDDA and DEDA-(PO) with the trivalent lanthanide and divalent metal ions (Table 4). These values take into account the ligand basicity and give an indication of the metal scavenging ability under simulated physiological conditions. These values are of particular importance when considering the applicability of a ligand scaffold toward medicinal uses (i.e., as an MRI contrast agent or radiopharmaceutical chelator). Although DEDA-(PO) demonstrates a substantially enhanced stability with the lanthanides compared to EDDA, it is unlikely that transchelation in vivo with biologically relevant metals could be avoided (particularly with copper). As such, DEDA-(PO) is not an appropriate ligand for testing in a metal pharmaceutical context. X-ray Crystal Structure of Cu2+-DEDA-(PO). The 1:1 copper(II) complex of DEDA-(PO) detected during potentiometric titrations was further characterized in the solid-state by Xray crystallography, small dark-blue crystals of which of which were obtained by the slow diffusion of a concentrated aqueous CuCl2 solution into an aqueous solution of the ligand

Table 2. Stability Constants for DEDA-(PO) As Determined by Potentiometric Titrations for La3+, Gd3+, and Lu3+ (25 °C and I = 0.16 M NaCl) Calculated from 1:1 and 1:2 M/L Experiments and Determined Using the Software HyerQuad201323,a DEDA-(PO) model LaL LaL2 LaL2(OH) GdL GdL(OH) GdL2 GdL2(OH) LuL LuL(OH) LuL(OH)2 LuL2

log β 10.01(6) 17.65(8) 7.18(7) 10.68(2) 1.89(3) 16.38(3) 5.5(1) 10.23(3) 0.62(1) −9.21(5) 14.99(7)

EDDA

log K

log β b

7.64 10.47

7, 7.01 11.77c

log K c

4.73

8.1,b 8.13c 8.79 5.7 10.88

14.21c

6.08

9.1,b 9.09c 9.61 9.83 4.76

17.57c

8.48

a

The results are compared to literature values for EDDA. Note that log β1 = log KML. bFrom ref 16 (25 °C and I = 0.1 M KNO3). cFrom ref 15 (25 °C and I = 0.1 M KNO3).

concurrent speciation diagrams are presented in the Supporting Information (Figures S1−S3). For all three metal ions, precipitation due to hydroxide species is observed at high pH (9−11) and the related experimental data at that pH interval were not included in the fitting. This observation is also seen with EDDA, the solution chemistry of which with Ln3+ is welldocumented.15,16 EDDA shows preference for the 1:2 complexes in which the ligand can coordinatively saturate the metal ion (e.g., log βLaL = 7.04; log βLaL2 = 11.77). A similar preference for the 1:2 complexes is shown in the case of DEDA-(PO) (e.g., log βLaL = 10.01; log βLaL2 = 17.65), and generally speaking, the stability constants of the Ln3+ complexes with DEDA-(PO) are greater than those of EDDA. This difference is presumably due to the greater denticity offered by a phosphinate-containing ligand. EDDA demonstrates a clear trend in increasing stability across the lanthanide series for both 1:1 and 1:2 M/L species (Figure 2;

Figure 2. Trend in the stability constants (log β) across the lanthanide series with Ln3+ for EDDA (refs 15 and16) and DEDA-(PO) (this study).

La3+ < Gd3+ < Lu3+).15,16 This trend is due to the decreasing ionic radii across the series from La3+ to Lu3+ as well as a slight increase in the relative hardness, leading to the formation of stronger, coordinatively saturated complexes. In the case of DEDA-(PO), the reverse trend is observed for the series of 1:2 species (Figure 2; La3+ > Gd3+ > Lu3+), which we hypothesize is due to increased steric hindrance from the phosphinate group, destabilizing the 10157

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Figure 3. Portions of the 1H NMR spectra of the La3+-DEDA-(PO) system at various pH values (400 MHz, 298 K): (a) 1:1 M/L molar ratio and [L] = 0.008 M; (b) 1:2 M/L molar ratio and [L] = 0.008 M. (A) La(DEDA-(PO)). (B) La(DEDA-(PO))23−.

preadjusted to pH 11 with 1 M KOH. The material crystallized with a potassium counterion and one uncoordinated water molecule in the asymmetric unit, giving the empirical formula K[Cu(DEDA-(PO))]·H2O (Figure 6 and Table S1). Each copper(II) is 5-coordinate, bonding the two carboxylate oxygen atoms and both nitrogen atoms from a single molecule of DEDA(PO). The fifth bond is between copper(II) and the phosphinate oxygen atom of a molecule occupying the adjacent asymmetric unit (not shown in Figure 6), thereby forming an extended lattice network throughout the structure (Figure S5). A list of selected interatomic distances and angles is presented in Table 5.

Table 3. Stability Constants (log KML) for Divalent Metal Ions with DEDA-(PO) As Calculated by Potentiometric Titrations (25 °C and I = 0.16 M NaCl) Using the Software HyperQuad201323 and Compared to the Literature Values for EDDA model

DEDA-(PO)

EDDA

log KCaL log KZnL log KZnL(OH) log KCuL log KCuL(OH)

4.67(1) 8.36(1) 10.14(3) 11.51(3) 10.73(3)

2.5a 11.2,b 10.99(1)c 10.56(4)c 16.3,a 16.2b

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a From ref 16 (25 °C and I = 0.1 M KNO3). bFrom ref 14 (30 °C and I = 0.1 M KNO3). cFrom ref 24 (25 °C and I = 0.1 M KNO3).

CONCLUSIONS A 7-membered heterocycle, DEDA-(PO), was synthesized and tested for its solution behavior with the trivalent lanthanides lanthanum, gadolinium, and lutetium. The selected lanthanide

Figure 4. UV−vis spectrophotometric titrations showing the shift in the absorbance maxima as the pH is raised (a) from 1.14 to 6.15 and (b) from 6.15 to 11.16. [Cu2+] = [L] = 3.21 × 10−3 M; 25 °C; path length = 1 cm. 10158

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resolution was provided in the form of a 1:1 copper(II) complex, K[Cu(DEDA-(PO))]·H2O. The potentiometry data presented in that study were repeated here with the same metal ions in order to correct the original manuscript. DEDA-(PO) was compared to the well-known ligand EDDA in its solution chemistry and chelation properties with the metal ions and was found to behave similarly in terms of metal-to-ligand stoichiometry. In all cases with Ln3+, the 1:2 complexes are the more stable species in solution versus the 1:1 complexes and are found to form preferentially at higher pH levels. The trend in the stability of 1:2 complexes across the lanthanide series was reversed for DEDA-(PO) compared to EDDA, possibly because of a steric effect caused by an additional binding metal−binding site (the phosphinate group), leading to a preference for the larger lanthanides. The pM values for the lanthanides with DEDA-(PO) were compared with the biologically relevant divalent metal ions and revealed that, similarly to EDDA, the ligand would be unlikely to bind and preferentially retain lanthanide ions in vivo.

Figure 5. Speciation diagram for the Cu2+-DEDA-(PO) system from potentiometric titrations. [Cu2+] = [L] = 1.1 × 10−3 M; 25 °C; I = 0.16 M (NaCl).

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Table 4. pM Values for EDDA and DEDA-(PO) with Trivalent Lanthanides and Divalent Metalsa Ca DEDA-(PO) EDDA

2+

6 6

Zn

2+

8.5 9.7

Cu

2+

11.6 14.9

3+

3+

La

Gd

11.80 6.20

11.02 6.92

Lu

3+

Materials, Reagents, and Instruments. All starting materials (EDDA, 50% w/w hypophosphorous acid, an 37% w/w formaldehyde) were purchased from commercial sources and used without further purification. Copper and lanthanum ions for NMR experiments were obtained from the hydrated chloride and nitrate salts, respectively, obtained from Alfa Aesar (CuCl2·2H2O, 99%; La(NO3)3·6H2O, 99.9%). Lanthanides and other metal-ion solutions for potentiometric titrations were prepared from the atomic absorption (AA) standard solution obtained from Sigma-Aldrich (∼1000 μg/mL M in 1 wt % HNO3). Solvents used in the washing/purification steps were of highperformance liquid chromatography grade and were obtained from Sigma-Aldrich. Water used in the synthesis was deionized (15 MΩ cm) and obtained from an Elga Purelab Option water purifier. D2O, NaOD, and DCl for NMR experiments were purchased from Cambridge Isotope Laboratories. NMR spectra were recorded on a Bruker AV400 instrument, referenced on the δ scale, and referenced either to residual solvent peaks or externally to H3PO4 in the case of 31P{1H} NMR. Lowresolution mass spectrometry was performed using a Waters/Micromass LCT instrument. High-resolution mass spectrometry was performed using a Kratos MS-50 instrument. Microanalyses for carbon, hydrogen, and nitrogen were carried out using a Carlo Erba EA 1108 elemental analyzer. X-ray crystallographic data were collected at −173.0 °C using a Bruker X8 Apex II diffractometer with graphitemonochromated Mo Kα radiation. Protonation and metal stability constants were calculated from potentiometric titrations that were undertaken using a Metrohm Titrando 809 equipped with a Ross combination pH electrode and a Metrohm Dosino 800 automatic buret. Data were collected using PC control (version 6.0.91, Metrohm). Temperature control was maintained using a Julabo water bath (25 ± 0.1 °C). The titration apparatus consisted of a 20 mL thermostated glass cell and an inlet−outlet tube for N2 gas (purified through a 10% NaOH solution) to exclude any CO2 during the course of the titration. UV−vis spectra were collected using a Cary 60 spectrophotometer. Synthesis and Characterization of H3DEDA-(PO)·HCl. N,N′Ethylenediaminediacetic acid (EDDA; 3.5 g, 20 mmol) was dissolved in 6 M HCl (20 mL) with hypophosphorous acid (50% w/w, 2.20 mL, 20 mmol) and heated to reflux. Formaldehyde (37% w/w, 6.4 mL, 80 mmol) was added dropwise over 1 h. After 4 h of reflux, a white precipitate evolved from the reaction mixture, which was collected on a fine frit and washed several times with 2−3 mL portions of cold methanol followed by cold acetone. High-vacuum drying overnight yielded H3DEDA-(PO)·HCl as a fluffy white solid (2.84 g, 9.4 mmol, 47% yield). ESI-TOF-MS negative-ion mode (m/z): 265.0 ([M − H]−). 1 H NMR (D2O, 400 MHz, RT): δ 4.07 (s, 4H), 4.01 (s, 4H), 3.65 (d, 4H, 2JHP = 12 Hz). 13C{1H} NMR (D2O, 400 MHz, RT): δ 174.1, 71.6, 63.4, 61.0. 31P{1H} NMR (D2O, 162 MHz, RT): δ 16. Anal. Calcd

10.94 8.92

pM = −log [Mfree] calculated at [Mn+] = 10−6 M, [L] = 10−5 M, and pH 7.4. a

Figure 6. ORTEP diagram of K[Cu(DEDA-(PO))]·H2O nonaqueous hydrogen atoms omitted for clarity. Associated crystallographic data are presented in Table S1 and an extended network structure in Figure S5.

Table 5. Selected Bond Distances and Angles for K[Cu(DEDA-(PO))]·H2O bond

length (Å)

angle

θ (deg)

Cu−N1 Cu−N2 Cu−O3 Cu−O6 Cu−O2′

2.0562(10) 2.0567(10) 2.2280(9) 1.9504(8) 1.9918(8)

N1−Cu−N2 N1−Cu−O6 N2−Cu−O3

81.41(4) 85.12(4) 75.84(3)

EXPERIMENTAL SECTION

ions have important potential therapeutic applications, particularly as diagnostic imaging agents. Consequently, the ligand was also tested with the biologically relevant dications copper, zinc, and calcium. An important result from the characterization data of the ligand (including an X-ray crystal structure) was the unequivocal proof that a previously published compound TETA(PO)2 was, in fact, misreported.10 Additional structural 10159

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(found) for C8H16ClN2O6P: C, 31.75 (31.88); H, 5.33 (5.31); N, 9.26 (9.11). X-ray Crystallography. H3DEDA-(PO)·3H2O. Colorless blade crystals suitable for single-crystal X-ray crystallographic analysis were obtained from a saturated aqueous solution cooled to 2 °C. The structure was solved by direct methods.25 The material crystallized with three water molecules in the asymmetric unit. All non-hydrogen atoms were refined anisotropically. All O−H and N−H hydrogen atoms were located in difference maps and refined isotropically. All other hydrogen atoms were placed in calculated positions. Further structural refinement details are available in the Supporting Information. K[Cu(DEDA-(PO))]·H2O. Blue prismatic crystals suitable for singlecrystal X-ray crystallographic analysis were obtained by the slow diffusion of a concentrated aqueous CuCl2 solution into an aqueous solution of the ligand preadjusted to pH 11 with 1 M KOH. The structure was solved by direct methods.25 The material crystallized with one water molecule in the asymmetric unit. All O−H hydrogen atoms were located in difference maps and refined isotropically. All other hydrogen atoms were placed in calculated positions. Further structural refinement details are available in the Supporting Information. Potentiometric Measurements. All data were collected in triplicate. Prior to each titration, the electrode was calibrated daily for hydrogen ion concentrations using standard HCl. Calibration data were analyzed with Gran’s procedure to obtain parameters E0 and pKw.26 The time allowed for equilibration was 1 min for pKa titrations and 2 min for metal−ligand titrations. Solutions were titrated with carbonate-free NaOH (0.156 M), which was standardized against freshly recrystallized potassium hydrogen phthalate. Protonation equilibria of the ligand were studied by NaOH titrations of a solution containing 1.1 × 10−3 M DEDA-(PO) and 4 equiv of HCl at 25 °C and 0.16 M NaCl ionic strength. In the study of the complex formation equilibria, the ligand− metal solutions were prepared by adding the AA standard metal-ion solution to a DEDA-(PO) solution of known concentration in the M/L molar ratios of 1:1 and 1:2 for all of the metal ions. Ligand and metal concentrations were in the range of 1−0.5 mM. The exact amount of acid present in the metal standards was determined by Gran’s method by titrating equimolar solutions of each metal and Na2H2EDTA.26 Potentiometric data were processed using HyperQuad2013 software.23 Proton dissociation constants corresponding to hydrolysis of all of the aqueous ions included in the calculations were taken from Baes and Mesmer.27 The species formed in the studied systems are characterized by the general equilibrium pM + qH + rL = MpHqLr (charges omitted). For convention, a complex containing metal ion M, proton H, and ligand L has the general formula MpHqLr. The stoichiometric index p might also be 0 in the case of protonation equilibria, and negative values of q refer to proton removal or hydroxide-ion addition during formation of the complex. The overall equilibrium constant for the formation of complexes from its components is designated as log β. Stepwise equilibrium constants log K correspond to the difference in log units between the overall constants of sequentially protonated (or hydroxide) species. pM is defined as (−log [Mn+]free) and calculated at specific conditions ([Mn+] = 1 μM, [Ln−] = 10 μM, pH 7.4, and 25 °C. UV−Vis Spectrophotometric Titrations. Spectra were collected in the spectral range 200−450 nm. Individual samples of 5 mL containing [Cu2+] = [L] = 3.21 × 10−3 M in pure water were adjusted to different pH values by the addition of different amounts of standardized HCl or NaOH. NaCl was added to maintain a constant ionic strength of 0.16 M. The path length was 1 cm for all of the samples. All spectra were collected at 25 °C and allowed to equilibrate for 5 min after the pH was adjusted and before the spectrum was recorded. NMR Measurements. The NMR spectra of the free ligand DEDA(PO) and the LaIII-L solutions ([DEDA-(PO)] = 0.008 M and La/L ratios 1:1 and 1:2) were recorded at different pH values. The pD was adjusted by adding DCl or NaOD, and the pD was calculated as pD = pH + 0.4.28

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b01117. Structural refinement data for the crystal structures of the DEDA-(PO) ligand and its copper(II) complex, speciation diagrams for Ln 3+ with DEDA-(PO) from potentiometric titrations in 1:1 and 1:2 molar ratios, 31 1 P{ H} NMR spectra of the 1:1 and 1:2 La/L samples at different pH levels, and extended-network structure for the CuII-DEDA-(PO) complex (PDF) Accession Codes

CCDC 1547499−1547500 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +16048224449. ORCID

Chris Orvig: 0000-0002-2830-5493 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge funding from the Natural Sciences and Engineering Research Council (NSERC) of Canada for grant support (CR&D, CHRP, and Discovery), the NSERC for a CGSD fellowship (to T.I.K.), and the Canadian Institutes of Health Research (CIHR) in two Collaborative Health Research Projects (CHRP). C.O. also thanks the Canada Council for the Arts for a Killam Research Fellowship (2011−2013).

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REFERENCES

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