Solution Structure of Ln(III) Complexes with Macrocyclic Ligands Through Theoretical Evaluation of ¹H NMR Contact Shifts

Herein, we present a new approach that combines DFT calculations and the analysis of Tb^III-induced ¹H NMR shifts to quantitatively and accurately account for the contact contribution to the paramagnetic shift in Ln^III complexes. Geometry optimizations of different Gd^III complexes with macrocyclic ligands were carried out using the hybrid meta-GGA TPSSh functional and a 46 + 4f⁷ effective core potential (ECP) for Gd. The complexes investigated include [Ln­(Me-DODPA)]⁺ (H₂Me-DODPA = 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid, [Ln­(DOTA)­(H₂O)]⁻ (H₄DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), [Ln­(DOTAM)­(H₂O)]³⁺ (DOTAM = 1,4,7,10- tetrakis­[(carbamoyl)­methyl]-1,4,7,10-tetraazacyclododecane), and related systems containing pyridyl units (Ln = Gd, Tb). Subsequent all-electron relativistic calculations based on the DKH2 approximation, or small-core ECP calculations, were used to compute the ¹H hyperfine coupling constants (HFCCs) at the ligand nuclei (<i>A</i>_iso values). The calculated <i>A</i>_iso values provided direct access to contact contributions to the ¹H NMR shifts of the corresponding Tb^III complexes under the assumption that Gd and Tb complexes with a given ligand present similar HFCCs. These contact shifts were used to obtain the pseudocontact shifts, which encode structural information as they depend on the position of the nucleus with respect to the lanthanide ion. An excellent agreement was observed between the experimental and calculated pseudocontact shifts using the DFT-optimized geometries as structural models of the complexes in solution, which demonstrates that the computational approach used provides (i) good structural models for the complexes, (ii) accurate HFCCs at the ligand nuclei. The methodology presented in this work can be classified in the context of model-dependent methods, as it relies on the use of a specific molecular structure obtained from DFT calculations. Our results show that spin polarization effects dominate the ¹H <i>A</i>_iso values. The X-ray crystal structures of [Ln­(Me-DODPA)]­(PF₆)·2H₂O (Ln = Eu or Lu) are also reported

Solution Structure of Ln(III) Complexes with Macrocyclic Ligands Through Theoretical Evaluation of ¹H NMR Contact Shifts

Herein, we present a new approach that combines DFT calculations and the analysis of Tb^III-induced ¹H NMR shifts to quantitatively and accurately account for the contact contribution to the paramagnetic shift in Ln^III complexes. Geometry optimizations of different Gd^III complexes with macrocyclic ligands were carried out using the hybrid meta-GGA TPSSh functional and a 46 + 4f⁷ effective core potential (ECP) for Gd. The complexes investigated include [Ln­(Me-DODPA)]⁺ (H₂Me-DODPA = 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid, [Ln­(DOTA)­(H₂O)]⁻ (H₄DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), [Ln­(DOTAM)­(H₂O)]³⁺ (DOTAM = 1,4,7,10- tetrakis­[(carbamoyl)­methyl]-1,4,7,10-tetraazacyclododecane), and related systems containing pyridyl units (Ln = Gd, Tb). Subsequent all-electron relativistic calculations based on the DKH2 approximation, or small-core ECP calculations, were used to compute the ¹H hyperfine coupling constants (HFCCs) at the ligand nuclei (<i>A</i>_iso values). The calculated <i>A</i>_iso values provided direct access to contact contributions to the ¹H NMR shifts of the corresponding Tb^III complexes under the assumption that Gd and Tb complexes with a given ligand present similar HFCCs. These contact shifts were used to obtain the pseudocontact shifts, which encode structural information as they depend on the position of the nucleus with respect to the lanthanide ion. An excellent agreement was observed between the experimental and calculated pseudocontact shifts using the DFT-optimized geometries as structural models of the complexes in solution, which demonstrates that the computational approach used provides (i) good structural models for the complexes, (ii) accurate HFCCs at the ligand nuclei. The methodology presented in this work can be classified in the context of model-dependent methods, as it relies on the use of a specific molecular structure obtained from DFT calculations. Our results show that spin polarization effects dominate the ¹H <i>A</i>_iso values. The X-ray crystal structures of [Ln­(Me-DODPA)]­(PF₆)·2H₂O (Ln = Eu or Lu) are also reported

Lanthanide(III) Complexes with Ligands Derived from a Cyclen Framework Containing Pyridinecarboxylate Pendants. The Effect of Steric Hindrance on the Hydration Number

Two new macrocyclic ligands, 6,6′-((1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂DODPA) and 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂Me-DODPA), designed for complexation of lanthanide ions in aqueous solution, have been synthesized and studied. The X-ray crystal structure of [Yb­(DODPA)]­(PF₆)·H₂O shows that the metal ion is directly bound to the eight donor atoms of the ligand, which results in a square-antiprismatic coordination around the metal ion. The hydration numbers (<i>q</i>) obtained from luminescence lifetime measurements in aqueous solution of the Eu^III and Tb^III complexes indicate that the DODPA complexes contain one inner-sphere water molecule, while those of the methylated analogue H₂Me-DODPA are <i>q</i> = 0. The structure of the complexes in solution has been investigated by ¹H and ¹³C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (DFT; mPWB95) level. The minimum energy conformation calculated for the Yb^III complex [Λ­(λλλλ)] is in good agreement with the experimental structure in solution, as demonstrated by the analysis of the Yb^III-induced paramagnetic ¹H shifts. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd­(Me-DODPA)]⁺ are typical of a complex with <i>q</i> = 0, where the observed relaxivity can be accounted for by the outer-sphere mechanism. However, [Gd­(DODPA)]⁺ shows NMRD profiles consistent with the presence of both inner- and outer-sphere contributions to relaxivity. A simultaneous fitting of the NMRD profiles and variable temperature ¹⁷O NMR chemical shifts and transversal relaxation rates provided the parameters governing the relaxivity in [Gd­(DODPA)]⁺. The results show that this system is endowed with a relatively fast water exchange rate <i>k</i>_<i>ex</i>²⁹⁸ = 58 × 10⁶ s^–1

Lanthanide(III) Complexes with Ligands Derived from a Cyclen Framework Containing Pyridinecarboxylate Pendants. The Effect of Steric Hindrance on the Hydration Number

Two new macrocyclic ligands, 6,6′-((1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂DODPA) and 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂Me-DODPA), designed for complexation of lanthanide ions in aqueous solution, have been synthesized and studied. The X-ray crystal structure of [Yb­(DODPA)]­(PF₆)·H₂O shows that the metal ion is directly bound to the eight donor atoms of the ligand, which results in a square-antiprismatic coordination around the metal ion. The hydration numbers (<i>q</i>) obtained from luminescence lifetime measurements in aqueous solution of the Eu^III and Tb^III complexes indicate that the DODPA complexes contain one inner-sphere water molecule, while those of the methylated analogue H₂Me-DODPA are <i>q</i> = 0. The structure of the complexes in solution has been investigated by ¹H and ¹³C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (DFT; mPWB95) level. The minimum energy conformation calculated for the Yb^III complex [Λ­(λλλλ)] is in good agreement with the experimental structure in solution, as demonstrated by the analysis of the Yb^III-induced paramagnetic ¹H shifts. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd­(Me-DODPA)]⁺ are typical of a complex with <i>q</i> = 0, where the observed relaxivity can be accounted for by the outer-sphere mechanism. However, [Gd­(DODPA)]⁺ shows NMRD profiles consistent with the presence of both inner- and outer-sphere contributions to relaxivity. A simultaneous fitting of the NMRD profiles and variable temperature ¹⁷O NMR chemical shifts and transversal relaxation rates provided the parameters governing the relaxivity in [Gd­(DODPA)]⁺. The results show that this system is endowed with a relatively fast water exchange rate <i>k</i>_<i>ex</i>²⁹⁸ = 58 × 10⁶ s^–1

Cooperative Anion Recognition in Copper(II) and Zinc(II) Complexes with a Ditopic Tripodal Ligand Containing a Urea Group

The ability of Cu^II and Zn^II complexes of the ditopic receptor H₂L [1-(2-((bis­(pyridin-2-ylmethyl)­amino)­methyl)­phenyl)-3-(3-nitrophenyl)­urea] for anion recognition is reported. In the presence of weakly coordinating anions such as ClO₄^–, the urea group binds to the metal ion (Cu^II or Zn^II) through one of its nitrogen atoms. The study of the interaction of the metal complexes with a variety of anions in DMSO shows that SO₄^2– and Cl^– bind to the complexes through a cooperative binding involving simultaneous coordination to the metal ion and different hydrogen-bonding interactions with the urea moiety, depending on the shape and size of the anion. On the contrary, single crystal X-ray diffraction studies show that anions such as NO₃^– and PhCO₂^– form 1:2 complexes (metal/anion) where one of the anions coordinates to the metal center and the second one is involved in hydrogen-bonding interaction with the urea group, which is projected away from the metal ion. Spectrophotometric titrations performed for the Cu^II complex indicate that this system is able to bind a wide range of anions with an affinity sequence: MeCO₂^– ∼ Cl^– (log <i>K</i>₁₁ > 7) > NO₂^– > H₂PO₄^– ∼ Br^– > HSO₄^– > NO₃^– (log <i>K</i>₁₁ < 2). In contrast to this, the free ligand gives much weaker interactions with these anions. In the presence of basic anions such as MeCO₂^– or F^–, competitive processes associated with the deprotonation of the coordinated N–H group of the urea moiety take place. Thus, N-coordination of the urea unit to the metal ion increases the acidity of one of its N–H groups. DFT calculations performed in DMSO solution are in agreement with both an anion-hydrogen bonding interaction and an anion–metal ion coordination collaborating in the stabilization of the metal salt complexes with tetrahedral anions

Cooperative Anion Recognition in Copper(II) and Zinc(II) Complexes with a Ditopic Tripodal Ligand Containing a Urea Group

The ability of Cu^II and Zn^II complexes of the ditopic receptor H₂L [1-(2-((bis­(pyridin-2-ylmethyl)­amino)­methyl)­phenyl)-3-(3-nitrophenyl)­urea] for anion recognition is reported. In the presence of weakly coordinating anions such as ClO₄^–, the urea group binds to the metal ion (Cu^II or Zn^II) through one of its nitrogen atoms. The study of the interaction of the metal complexes with a variety of anions in DMSO shows that SO₄^2– and Cl^– bind to the complexes through a cooperative binding involving simultaneous coordination to the metal ion and different hydrogen-bonding interactions with the urea moiety, depending on the shape and size of the anion. On the contrary, single crystal X-ray diffraction studies show that anions such as NO₃^– and PhCO₂^– form 1:2 complexes (metal/anion) where one of the anions coordinates to the metal center and the second one is involved in hydrogen-bonding interaction with the urea group, which is projected away from the metal ion. Spectrophotometric titrations performed for the Cu^II complex indicate that this system is able to bind a wide range of anions with an affinity sequence: MeCO₂^– ∼ Cl^– (log <i>K</i>₁₁ > 7) > NO₂^– > H₂PO₄^– ∼ Br^– > HSO₄^– > NO₃^– (log <i>K</i>₁₁ < 2). In contrast to this, the free ligand gives much weaker interactions with these anions. In the presence of basic anions such as MeCO₂^– or F^–, competitive processes associated with the deprotonation of the coordinated N–H group of the urea moiety take place. Thus, N-coordination of the urea unit to the metal ion increases the acidity of one of its N–H groups. DFT calculations performed in DMSO solution are in agreement with both an anion-hydrogen bonding interaction and an anion–metal ion coordination collaborating in the stabilization of the metal salt complexes with tetrahedral anions

Lanthanide(III) Complexes with a Reinforced Cyclam Ligand Show Unprecedented Kinetic Inertness

Lanthanide­(III) complexes of a cross-bridged cyclam derivative containing two picolinate pendant arms are kinetically inert in very harsh conditions such as 2 M HCl, with no dissociation being observed for at least 5 months. Importantly, the [Ln­(dota)]⁻ complexes, which are recognized to be extremely inert, dissociate under these conditions with lifetimes in the range ca. 1 min to 12 h depending upon the Ln³⁺ ion. X-ray diffraction studies reveal octadentate binding of the ligand to the metal ion in the [Eu­(cb-tedpa)]⁺ complex, while ¹H and ¹³C NMR experiments in D₂O point to the presence of a single diastereoisomer in solution with a very rigid structure. The structure of the complexes in the solid state is retained in solution, as demonstrated by the analysis of the Yb³⁺-induced paramagnetic shifts

Complexation of Ln³⁺ Ions with Cyclam Dipicolinates: A Small Bridge that Makes Huge Differences in Structure, Equilibrium, and Kinetic Properties

The coordination properties toward the lanthanide ions of two macrocyclic ligands based on a cyclam platform containing picolinate pendant arms have been investigated. The synthesis of the ligands was achieved by using the well-known bis-aminal chemistry. One of the cyclam derivatives (cb-tedpa^2–) is reinforced with a cross-bridge unit, which results in exceptionally inert [Ln­(cb-tedpa)]⁺ complexes. The X-ray structures of the [La­(cb-tedpa)­Cl], [Gd­(cb-tedpa)]⁺, and [Lu­(Me₂tedpa)]⁺ complexes indicate octadentate binding of the ligands to the metal ions. The analysis of the Yb³⁺-induced shifts in [Yb­(Me₂tedpa)]⁺ indicates that this complex presents a solution structure very similar to that observed in the solid state for the Lu³⁺ analogue. The X-ray structures of [La­(H₂Me₂tedpa)₂]³⁺ and [Yb­(H₂Me₂tedpa)₂]³⁺ complexes confirm the exocyclic coordination of the metal ions, which gives rise to coordination polymers with the metal coordination environment being fulfilled by oxygen atoms of the picolinate groups and water molecules. The X-ray structure of [Gd­(Hcb-tedpa)₂]⁺ also indicates exocyclic coordination that in this case results in a discrete structure with an eight-coordinated metal ion. The nonreinforced complexes [Ln­(Me₂tedpa)]⁺ were prepared and isolated as chloride salts in nonaqueous media. However, these complexes were found to undergo dissociation in aqueous solution, except in the case of the complexes with the smallest Ln³⁺ ions (Ln³⁺ = Yb³⁺ and Lu³⁺). A DFT investigation shows that the increased stability of the [Ln­(Me₂tedpa)]⁺ complexes in solution across the lanthanide series is the result of an increased binding energy of the ligand due to the increased charge density of the Ln³⁺ ion

Stabilizing Divalent Europium in Aqueous Solution Using Size-Discrimination and Electrostatic Effects

We report two macrocyclic ligands containing a 1,10-diaza-18-crown-6 fragment functionalized with either two picolinamide pendant arms (bpa18c6) or one picolinamide and one picolinate arm (ppa18c6^–). The X-ray structure of [La­(ppa18c6)­(H₂O)]²⁺ shows that the ligand binds to the metal ion using the six donor atoms of the crown moiety and the four donor atoms of the pendant arms, 11-coordination being completed by the presence of a coordinated water molecule. The X-ray structure of the [Sr­(bpa18c6)­(H₂O)]²⁺ was also investigated due to the very similar ionic radii of Sr²⁺ and Eu²⁺. The structure of this complex is very similar to that of [La­(ppa18c6)­(H₂O)]²⁺, with the metal ion being 11-coordinated. Potentiometric measurements were used to determine the stability constants of the complexes formed with La³⁺ and Eu³⁺. Both ligands present a very high selectivity for the large La³⁺ ion over the smaller Eu³⁺, with a size-discrimination ability that exceeds that of the analogous ligand containing two picolinate pendant arms reported previously (bp18c6^2–). DFT calculations using the TPSSh functional and the large-core pseudopotential approximation provided stability trends in good agreement with the experimental values, indicating that charge neutral ligands derived from 1,10-diaza-18-crown-6 enhance the selectivity of the ligand for the large Ln³⁺ ions. Cyclic voltammetry measurements show that the stabilization of Eu²⁺ by these ligands follows the sequence bp18c6^2– < ppa18c6^– < bpa18c6 with half-wave potentials of −753 mV (bp18c6^2–), −610 mV (ppa18c6^–), and −453 mV (bpa18c6) versus Ag/AgCl. These values reveal that the complex of bpa18c6 possesses higher stability against oxidation than the aquated ion, for which an <i>E</i>_1/2 value of −585 mV has been measured

Mono‑, Bi‑, and Trinuclear Bis-Hydrated Mn²⁺ Complexes as Potential MRI Contrast Agents

We report a series of ligands containing pentadentate 6,6′-((methylazanediyl)­bis­(methylene))­dipicolinic acid binding units that form mono- (H₂dpama), di- (<i>m</i>X­(H₂dpama)₂), and trinuclear (<i>m</i>X­(H₂dpama)₃) complexes with Mn²⁺ containing two coordinated water molecules per metal ion, which results in pentagonal bipyramidal coordination around the metal ions. In contrast, the hexadentate ligand 6,6′-((ethane-1,2-diylbis­(azanediyl))­bis­(methylene))­dipicolinic acid (H₂bcpe) forms a complex with distorted octahedral coordination around Mn²⁺ that lacks coordinated water molecules. The protonation constants of the ligands and the stability constants of the Mn²⁺, Cu²⁺, and Zn²⁺ complexes were determined using potentiometric and spectrophotometric titrations in 0.15 M NaCl. The pentadentate dpama^2– ligand and the di- and trinucleating mX­(dpama)₂^4– and mX­(dpama)₃^6– ligands provide metal complexes with stabilities that are very similar to that of the complex with the hexadentate ligand bcpe^2–, with log β₁₀₁ values in the range 10.1–11.6. Cyclic voltammetry experiments on aqueous solutions of the [Mn­(bcpe)] complex reveal a quasireversible system with a half-wave potential of +595 mV versus Ag/AgCl. However, [Mn­(dpama)] did not suffer oxidation in the range 0.0–1.0 V, revealing a higher resistance toward oxidation. A detailed ¹H NMRD and ¹⁷O NMR study provided insight into the parameters that govern the relaxivity for these systems. The exchange rate of the coordinated water molecules in [Mn­(dpama)] is relatively fast, <i>k</i>_ex²⁹⁸ = (3.06 ± 0.16) × 10⁸ s^–1. The trinuclear [mX­(Mn­(dpama)­(H₂O)₂)₃] complex was found to bind human serum albumin with an association constant of 1286 ± 55 M^–1 and a relaxivity of the adduct of 45.2 ± 0.6 mM^–1 s^–1 at 310 K and 20 MHz