Toward the Prediction of Water Exchange Rates in Magnetic Resonance Imaging Contrast Agents: A Density Functional Theory Study

We present a theoretical investigation of Gd–O_water bonds in different complexes relevant as contrast agents in magnetic resonance imaging (MRI). The analysis of the Ln–O_water distances, electron density (ρ_BCP), and electron localization function (ELF) at the bond critical points of [Ln­(DOTA)­(H₂O)]⁻ and [Ln­(DTPA-BMA)­(H₂O)] indicates that the strength of the Ln–O_water bonds follows the order DTPA-BMA > DOTA (<b>M</b> isomer) > DOTA (<b>m</b> isomer). The ELF values decrease along the 4f period as the Ln–O_water bonds get shorter, in line with the labile capping bond phenomenon. Extension of these calculations to other Gd³⁺ complexes allowed us to correlate the experimentally observed water exchange rates and the calculated ρ_BCP and ELF values. The water exchange reaction becomes faster as the Gd–O_water bonds are weakened, which is reflected in longer bond distances and lower values of ρ_BCP and ELF. DKH2 calculations show that the two coordinated water molecules may also have significantly different ¹⁷O hyperfine coupling constants (HFCCs)

Magnetic Anisotropy in Functionalized Bipyridyl Cryptates

The magnetic properties of molecular lanthanoid complexes are very important for a variety of scientific and technological applications, with the unique magnetic anisotropy being one of the most important features. In this context, a very rigid tris­(bipyridine) cryptand was synthesized with a primary amine functionality for future bioconjugation. The magnetic anisotropy was investigated for the corresponding paramagnetic ytterbium cryptate. With the use of a combination of density functional theory calculations and lanthanoid-induced NMR shift analysis, the magnetic susceptibility tensor was determined and compared to the unfunctionalized cryptate analogue. The size and orientation of the axial and rhombic tensor components show remarkably great resilience toward the decrease of local symmetry around the metal and anion exchange in the inner coordination sphere. In addition, the functionalized ytterbium cryptate also exhibits efficient near-IR luminescence

Long Wavelength Excitation of Europium Luminescence in Extended, Carboline-Based Cryptates

Two new β-carboline-based tris­(biaryl) europium cryptates are introduced. The extended antenna moiety incorporated into the cryptand frameworks enables the sensitization of europium emission with excitation wavelengths well above 450 nm. In aqueous solution, the cryptates show great complex stability, luminescence lifetimes around 0.5 ms, and absolute quantum yields of ca. 3%. In addition, the europium luminescence shows a well-defined pH-dependence in the physiologically interesting pH range 7–9

Complexation of [Gd(DTTA–Me)(H₂O)₂]⁻ by Fluoride and Its Consequences to Water Exchange

The displacement of water molecule(s) from the inner coordination sphere of [Gd­(DTTA–Me)­(H₂O)₂]⁻ (DTTA = ethylenetriamine-<i>N</i>,<i>N</i>,<i>N</i>″,<i>N</i>″-tetraacetate) by fluoride has been studied by multinuclear NMR relaxation (¹H, ¹⁷O, ¹⁹F) and DFT calculations. Fluoride anions can replace only one of the coordinated water molecules. The thermodynamic stability constant (<i>K</i>_GdLF,298⁰ = 11.6 ± 0.3) and thermodynamic parameters characterizing the formation of [Gd­(DTTA–Me)­(H₂O)­F]^2– were determined (Δ<i>H</i>⁰ = +6.3 ± 0.1 kJ mol^–1; Δ<i>S</i>⁰ = +41.5 ± 3.4 J mol^–1 K^–1; Δ<i>V</i>⁰ = +4.5 ± 1.2 cm³ mol^–1). Fluoride binding causes a marked acceleration of the water exchange, which is seven times faster for [Gd­(DTTA–Me)­(H₂O)­F]^2– (<i>k</i>_ex,1²⁹⁸ = 177 × 10⁶ s^–1) than for [Gd­(DTTA–Me)­(H₂O)₂]⁻ (<i>k</i>_ex,2²⁹⁸ = 24.6 × 10⁶ s^–1). Water exchange on both compounds is faster than formation of the fluoride complex. The analysis of the Gd–O_water distances, electron density, and electron localization function (ELF) at the bond critical points using DFT calculations reveals that F^– binding weakens the Gd–O_water bonds, thereby facilitating the departure of the coordinated water molecule following a dissociative mechanism. The water exchange on both Gd­(DTTA–Me) complexes follow dissociative reaction pathways as shown by the positive activation volumes Δ<i>V</i>^⧧ = +8 ± 2 cm³ mol^–1 and +15 ± 4 cm³ mol^–1 for the bis-aqua complex and the monofluoro complex, respectively

¹H and ¹⁷O NMR Relaxometric and Computational Study on Macrocyclic Mn(II) Complexes

Herein we report a detailed ¹H and ¹⁷O relaxometric investigation of Mn­(II) complexes with cyclen-based ligands such as 2-(1,4,7,10-tetraazacyclododecan-1-yl)­acetic acid (DO1A), 2,2′-(1,4,7,10-tetraazacyclododecane-1,4-diyl)­diacetic acid (1,4-DO2A), 2,2′-(1,4,7,10-tetraazacyclododecane-1,7-diyl)­diacetic acid (1,7-DO2A), and 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)­triacetic acid (DO3A). The Mn­(II) complex with the heptadentate ligand DO3A does not have inner sphere water molecules (<i>q</i> = 0), and therefore, the metal ion is most likely seven-coordinate. The hexadentate DO2A ligand has two isomeric forms: 1,7-DO2A and 1,4-DO2A. The Mn­(II) complex with 1,7-DO2A is predominantly six-coordinate (<i>q</i> = 0). In aqueous solutions of [Mn­(1,4-DO2A)], a species with one coordinated water molecule (<i>q</i> = 1) prevails largely, whereas a <i>q</i> = 0 form represents only about 10% of the overall population. The Mn­(II) complex of the pentadentate ligand DO1A also contains a coordinated water molecule. DFT calculations (B3LYP model) are used to obtain information about the structure of this family of closely related complexes in solution, as well as to determine theoretically the ¹⁷O and ¹H hyperfine coupling constants responsible for the scalar contribution to ¹⁷O and ¹H NMR relaxation rates and ¹⁷O NMR chemical shifts. These calculations provide ¹⁷O <i>A</i>/ℏ values of ca. 40 × 10⁶ rad s^–1, in good agreement with experimental data. The [Mn­(1,4-DO2A)­(H₂O)] complex is endowed with a relatively fast water exchange rate (<i>k</i>_ex²⁹⁸ = 11.3 × 10⁸ s^–1) in comparison to the [Mn­(EDTA)­(H₂O)]^2‑ analogue (<i>k</i>_ex²⁹⁸ = 4.7 × 10⁸ s^–1), but about 5 times lower than that of the [Mn­(DO1A)­(H₂O)]⁺ complex (<i>k</i>_ex²⁹⁸ = 60 × 10⁸ s^–1). The water exchange rate measured for the latter complex represents the highest water exchange rate ever measured for a Mn­(II) complex

¹⁷O NMR and Density Functional Theory Study of the Dynamics of the Carboxylate Groups in DOTA Complexes of Lanthanides in Aqueous Solution

The rotation of the carboxylate groups in DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) complexes of several lanthanide ions and Sc³⁺ was investigated with density functional theory (DFT) calculations and with variable temperature ¹⁷O NMR studies at 4.7–18.8 T. The data obtained show that the rotation is much slower than the other dynamic processes taking place in these complexes. The exchange between the bound and unbound carboxylate oxygen atoms for the largest Ln³⁺ ions (La³⁺→Sm³⁺) follows a pathway via a transition state in which both oxygens of the carboxylate group are bound to the Ln³⁺ ion, whereas for the smaller metal ions (Tm³⁺, Lu³⁺, Sc³⁺) the transition state has a fully decoordinated carboxylate group. The activation free energies show a steady increase from about 75 to 125–135 kJ·mol^–1 going from La³⁺ to Lu³⁺. This computed trend is consistent with the results of the ¹⁷O NMR measurements. Fast exchange between bound and unbound carboxylate oxygen atoms was observed for the diamagnetic La-DOTA, whereas for Pr-, Sm-, Lu-, and Sc-DOTA the exchange was slow on the NMR time scale. The trends in the linewidths for the various metal ions as a function of the temperature agree with trends in the rates as predicted by the DFT calculations

Monopicolinate Cyclen and Cyclam Derivatives for Stable Copper(II) Complexation

The syntheses of a new 1,4,7,10-tetraazacyclododecane (cyclen) derivative bearing a picolinate pendant arm (H<b>L1</b>), and its 1,4,8,11-tetraazacyclotetradecane (cyclam) analogue H<b>L2</b>, were achieved by using two different selective-protection methods involving the preparation of cyclen-bisaminal or phosphoryl cyclam derivatives. The acid–base properties of both compounds were investigated as well as their coordination chemistry, especially with Cu²⁺, in aqueous solution and in solid state. The copper­(II) complexes were synthesized, and the single crystal X-ray diffraction structures of compounds of formula [Cu­(HL)]­(ClO₄)₂·H₂O (L = <b>L1</b> or <b>L2</b>), [Cu<b>L1</b>]­(ClO₄) and [Cu<b>L2</b>]­Cl·2H₂O, were determined. These studies revealed that protonation of the complexes occurs on the carboxylate group of the picolinate moiety. Stability constants of the complexes were determined at 25.0 °C and ionic strength 0.10 M in KNO₃ using potentiometric titrations. Both ligands form complexes with Cu²⁺ that are thermodynamically very stable. Additionally, both H<b>L1</b> and H<b>L2</b> exhibit an important selectivity for Cu²⁺ over Zn²⁺. The kinetic inertness in acidic medium of both complexes of Cu²⁺ was evaluated by spectrophotometry revealing that [Cu<b>L2</b>]⁺ is much more inert than [Cu<b>L1</b>]⁺. The determined half-life values also demonstrate the very high kinetic inertness of [Cu<b>L2</b>]⁺ when compared to a list of copper­(II) complexes of other macrocyclic ligands. The coordination geometry of the copper center in the complexes was established in aqueous solution from UV–visible and electron paramagnetic resonance (EPR) spectroscopy, showing that the solution structures of both complexes are in excellent agreement with those of crystallographic data. Cyclic voltammetry experiments point to a good stability of the complexes with respect to metal ion dissociation upon reduction of the metal ion to Cu⁺ at about neutral pH. Our results revealed that the cyclam-based ligand H<b>L2</b> is a very attractive receptor for copper­(II), presenting a fast complexation process, a high kinetic inertness, and important thermodynamic and electrochemical stability

Investigating the Complexation of the Pb²⁺/Bi³⁺ Pair with Dipicolinate Cyclen Ligands

The complexation properties toward Pb²⁺ and Bi³⁺ of the macrocyclic ligands 6,6′-((1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂<b>do2pa</b>) and 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂<b>Me-do2pa</b>) have been investigated. A new three-step synthesis of H₂<b>do2pa</b> following the bisaminal methodology has also been developed. The X-ray structures of [Pb­(<b>Me-do2pa</b>)]·6H₂O and [Bi­(<b>Me-do2pa</b>)]­(NO₃)·H₂O show that the two metal ions are eight-coordinated by the ligand. The two complexes exist as the racemic Δ­(δδδδ)/Λ­(λλλλ) mixture both in the solid state and in solution, as indicated by NMR and DFT studies. The stability constants of the lead­(II) and bismuth­(III) complexes of the two ligands were determined in 0.5 M KCl using potentiometric and spectrophotometric techniques. The stability constants determined for the complexes of Pb²⁺ are relatively high (log <i>K</i>_ML = 16.44 and 18.44 for H₂<b>do2pa</b> and H₂<b>Me-do2pa</b>, respectively) and exceptionally high for the complexes of Bi³⁺ (log <i>K</i>_ML = 32.0 and 34.2 for H₂<b>do2pa</b> and H₂<b>Me-do2pa</b>, respectively). The [Pb­(<b>Me-do2pa</b>)] complex presents rather fast formation and very good kinetic inertness toward transchelation. Additionally, the [Bi­(<b>Me-do2pa</b>)]⁺ complex was found to present a remarkably fast complexation rate (full complexation in ∼2 min at pH 5.0, acetate buffer) and a very good kinetic inertness with respect to metal ion dissociation (half-life of 23.9 min in 1 M HCl), showing promise for potential applications in α-radioimmunotherapy

Monopicolinate Cyclen and Cyclam Derivatives for Stable Copper(II) Complexation

The syntheses of a new 1,4,7,10-tetraazacyclododecane (cyclen) derivative bearing a picolinate pendant arm (H<b>L1</b>), and its 1,4,8,11-tetraazacyclotetradecane (cyclam) analogue H<b>L2</b>, were achieved by using two different selective-protection methods involving the preparation of cyclen-bisaminal or phosphoryl cyclam derivatives. The acid–base properties of both compounds were investigated as well as their coordination chemistry, especially with Cu²⁺, in aqueous solution and in solid state. The copper­(II) complexes were synthesized, and the single crystal X-ray diffraction structures of compounds of formula [Cu­(HL)]­(ClO₄)₂·H₂O (L = <b>L1</b> or <b>L2</b>), [Cu<b>L1</b>]­(ClO₄) and [Cu<b>L2</b>]­Cl·2H₂O, were determined. These studies revealed that protonation of the complexes occurs on the carboxylate group of the picolinate moiety. Stability constants of the complexes were determined at 25.0 °C and ionic strength 0.10 M in KNO₃ using potentiometric titrations. Both ligands form complexes with Cu²⁺ that are thermodynamically very stable. Additionally, both H<b>L1</b> and H<b>L2</b> exhibit an important selectivity for Cu²⁺ over Zn²⁺. The kinetic inertness in acidic medium of both complexes of Cu²⁺ was evaluated by spectrophotometry revealing that [Cu<b>L2</b>]⁺ is much more inert than [Cu<b>L1</b>]⁺. The determined half-life values also demonstrate the very high kinetic inertness of [Cu<b>L2</b>]⁺ when compared to a list of copper­(II) complexes of other macrocyclic ligands. The coordination geometry of the copper center in the complexes was established in aqueous solution from UV–visible and electron paramagnetic resonance (EPR) spectroscopy, showing that the solution structures of both complexes are in excellent agreement with those of crystallographic data. Cyclic voltammetry experiments point to a good stability of the complexes with respect to metal ion dissociation upon reduction of the metal ion to Cu⁺ at about neutral pH. Our results revealed that the cyclam-based ligand H<b>L2</b> is a very attractive receptor for copper­(II), presenting a fast complexation process, a high kinetic inertness, and important thermodynamic and electrochemical stability

Lanthanide(III) Complexation with an Amide Derived Pyridinophane

Herein we report a detailed investigation of the solid state and solution structures of lanthanide­(III) complexes with the 18-membered pyridinophane ligand containing acetamide pendant arms TPPTAM (TPPTAM = 2,2′,2″-(3,7,11-triaza-1,5,9­(2,6)-tripyridinacyclododecaphane-3,7,11-triyl)­triacetamide). The ligand crystallizes in the form of a clathrated hydrate, where the clathrated water molecule establishes hydrogen-bonding interactions with the amide NH groups and two N atoms of the macrocycle. The X-ray structures of 13 different Ln³⁺ complexes obtained as the nitrate salts (Ln³⁺ = La³⁺–Yb³⁺, except Pm³⁺) have been determined. Additionally, the X-ray structure of the La³⁺ complex obtained as the triflate salt was also obtained. In all cases the ligand provides 9-fold coordination to the Ln³⁺ ion, ten coordination being completed by an oxygen atom of a coordinated water molecule or a nitrate or triflate anion. The bond distances of the metal coordination environment show a quadratic change along the lanthanide series, as expected for isostructural series of Ln³⁺ complexes. Luminescence lifetime measurements obtained from solutions of the Eu³⁺ and Tb³⁺ complexes in H₂O and D₂O point to the presence of a water molecule coordinated to the metal ion in aqueous solutions. The analysis of the Ln³⁺-induced paramagnetic shifts indicates that the complexes are ten-coordinated throughout the lanthanide series from Ce³⁺ to Yb³⁺, and that the solution structure is very similar to the structures observed in the solid state. The complexes of the light Ln³⁺ ions are fluxional due to a fast Δ­(λλλλλλ) ↔ Λ­(δδδδδδ) interconversion that involves the inversion of the macrocyclic ligand and the rotation of the acetamide pendant arms. The complexes of the small Ln³⁺ ions are considerably more rigid, the activation free energy determined from VT ¹H NMR for the Lu³⁺ complex being Δ<i>G</i>^⧧₂₉₈ = 72.4 ± 5.1 kJ mol^–1