Tuning Magnetic and Photophysical Properties of Luminomagnetic Metal-Organic Framework Composites in an Inverse Core-Satellite Structure.

Luminomagnetic composites have been synthesized that allow for an individual tuning of luminescence intensity, chromaticity and magnetization by combination of superparamagnetic, citrate-stabilized iron oxide nanoparticles with the luminescent MOFs 3 ∞ [Ln2 (BDC)3 (H2 O)4 ] (Ln=Eu, Tb; BDC2- =terephthalate). The components are arranged to a concept of inverse structuring compared to previous luminomagnetic composites with MOF@magnetic particle (shell@core) composition so that the luminescent MOF now acts as core and is covered by magnetic nanoparticles forming the satellite shell. Thereby, the magnetic and photophysical properties are individually tuneable between high emission intensity (1.2 ⋅ 106  cps mg-1 ) plus low saturation magnetization (6 emu g-1 ) and the direct opposite (0.09 ⋅ 106  cps mg-1 ; 42 emu g-1 ) by adjusting the particle coverage of the MOF. This is not achievable with a core-shell structure having a magnetic core and a dense MOF shell. The composition of the composites and the influence of different synthesis conditions on their properties were investigated by SEM/EDX, PXRD, magnetization measurements and photoluminescence spectroscopy.

Versatile Macrocyclic Platform for the Complexation of [natY/90Y]Yttrium and Lanthanide Ions.

We report a macrocyclic ligand (H3L6) based on a 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane platform containing three acetate pendant arms and a benzyl group attached to the fourth nitrogen atom of the macrocycle. The X-ray structures of the YL6 and TbL6 complexes reveal nine coordination of the ligand to the metal ions through the six nitrogen atoms of the macrocycle and three oxygen atoms of the carboxylate pendants. A combination of NMR spectroscopic studies (1H, 13C, and 89Y) and DFT calculations indicated that the structure of the YL6 complex in the solid state is maintained in an aqueous solution. The detailed study of the emission spectra of the EuL6 and TbL6 complexes revealed Ln3+-centered emission with quantum yields of 7.0 and 60%, respectively. Emission lifetime measurements indicate that the ligand offers good protection of the metal ions from surrounding water molecules, preventing the coordination of water molecules. The YL6 complex is remarkably inert with respect to complex dissociation, with a lifetime of 1.7 h in 1 M HCl. On the other hand, complex formation is fast (∼1 min at pH 5.4, 2 × 10-5 M). Studies using the 90Y-nuclide confirmed fast radiolabeling since [90Y]YL6 is nearly quantitatively formed (radiochemical yield (RCY) > 95) in a short time over a broad range of pH values from ca. 2.4 to 9.0. Challenging experiments in the presence of excess ethylenediaminetetraacetic acid (EDTA) and in human serum revealed good stability of the [90Y]YL6 complex. All of these experiments combined suggest the potential application of H3L6 derivatives as Y-based radiopharmaceuticals.

Unexpected Trends in the Stability and Dissociation Kinetics of Lanthanide(III) Complexes with Cyclen-Based Ligands across the Lanthanide Series.

We report a detailed study of the thermodynamic stability and dissociation kinetics of lanthanide complexes with two ligands containing a cyclen unit, a methyl group, a picolinate arm, and two acetate pendant arms linked to two nitrogen atoms of the macrocycle in either cis (1,4-H3DO2APA) or trans (1,7-H3DO2APA) positions. The stability constants of the Gd3+ complexes with these two ligands are very similar, with log KGdL values of 16.98 and 16.33 for the complexes of 1,4-H3DO2APA and 1,7-H3DO2APA, respectively. The stability constants of complexes with 1,4-H3DO2APA follow the usual trend, increasing from log KLaL = 15.96 to log KLuL = 19.21. However, the stability of [Ln(1,7-DO2APA)] complexes decreases from log K = 16.33 for Gd3+ to 14.24 for Lu3+. The acid-catalyzed dissociation rates of the Gd3+ complexes differ by a factor of ∼15, with rate constants (k1) of 1.42 and 23.5 M-1 s-1 for [Gd(1,4-DO2APA)] and [Gd(1,7-DO2APA)], respectively. This difference is magnified across the lanthanide series to reach a 5 orders of magnitude higher k1 for [Yb(1,7-DO2APA)] (1475 M-1 s-1) than for [Yb(1,4-DO2APA)] (5.79 × 10-3 M-1 s-1). The acid-catalyzed mechanism involves the protonation of a carboxylate group, followed by a cascade of proton-transfer events that result in the protonation of a nitrogen atom of the cyclen unit. Density functional theory calculations suggest a correlation between the strength of the Ln-Ocarboxylate bonds and the kinetic inertness of the complex, with stronger bonds providing more inert complexes. The 1H NMR resonance of the coordinated water molecule in the [Yb(1,7-DO2APA)] complex at 176 ppm provides a sizable chemical exchange saturation transfer effect thanks to a slow water exchange rate of (15.9 ± 1.6) × 103 s-1.

Lanthanide Complexes with 1H paraCEST and 19F Response for Magnetic Resonance Imaging Applications.

We present a detailed study of the lanthanide(III) complexes with cyclen-based ligands containing phenylacetamide pendants that incorporate CF3 group(s) at different distances from the metal ion. The complexes exhibit square-antiprismatic coordination in solution, as demonstrated by analysis of the Yb3+-induced paramagnetic shifts and the X-ray structure of the [YbL3] complex. Luminescence lifetime measurements and a detailed 1H and 17O relaxometric characterization confirmed the presence of an inner-sphere H2O molecule. The Tm3+ complexes provide chemical-exchange saturation-transfer response upon saturation at the frequency of the amide protons. A 19F relaxation study provided accurate estimates of the Ln···F distances that were used to rationalize the efficiency of the complexes as 19F magnetic resonance imaging (MRI) probes, which was tested in vitro using MRI phantom studies.

Reinforced Ni(ii)-cyclam derivatives as dual 1H/19F MRI probes.

Reinforced cross-bridged Ni2+-cyclam complexes were functionalised with pendant arms containing both amide protons and CF3 groups that lead to a dual 1H/19F response. The resulting complexes possess very high inertness favourable for MRI applications. The paramagnetism of the Ni2+ ion shifts the amide resonance 56 ppm away from bulk water favouring the chemical exchange saturation transfer (CEST) effect and shortening the acquisition times in 19F magnetic resonance imaging (MRI) experiments, thus enhancing the signal-to-noise ratios compared to the fluorinated diamagnetic reference.

Controlling water exchange rates in potential Mn2+-based MRI agents derived from NO2A2.

We report a series of pentadentate ligands based on a 1,4,7-triazacyclononane-1,4-diacetic acid (H2NO2A) containing different substituents attached to the third nitrogen atom of the macrocyclic unit. Detailed 1H Nuclear Magnetic Relaxation Dispersion (NMRD) characterisation of the corresponding Mn2+ complexes suggests the formation of six-coordinate species in solution containing an inner-sphere water molecule. This was confirmed by recording the transverse 17O relaxation time and chemical shift measurements. The water exchange rate of the coordinated water molecule was found to be strongly influenced by the nature of the substituent R at position 7 of the triazacyclononane unit (R = Me, k298ex = 62.6 × 107 s-1; R = Bz, k298ex = 4.4 × 107 s-1; R = 1-phenylethyl, k298ex = 2.6 × 107 s-1). The decreasing exchange rates are explained by the increasing bulkiness of the substituent, which hinders the approach of the entering water molecule in an associatively activated water exchange mechanism. This is supported by DFT calculations (M062X/TZVP), which confirm the associative nature of the water exchange reaction. A potentially decadentate ligand containing two NO2A units linked by a xylenyl spacer in the meta position was also synthesised. The corresponding binuclear Mn2+ complex contains two metal ions with different hydration numbers, as evidenced by 1H NMRD and 17O NMR measurements. DFT calculations show that this is related to the presence of a bridging bidentate µ-η1-carboxylate group connecting the two metal centers. The results reported in this work provide a straightforward strategy to control the exchange rate of the coordinated water molecule in this family of MRI contrast agent candidates.

Gadolinium(III)-Based Dual 1 H/19 F Magnetic Resonance Imaging Probes.

We present two novel octadentate cyclen-based ligands bearing one (L1 ) or two (L2 ) phenylacetamide pendants with two CF3 groups either at positions 3 and 5 (L1 ) or 4 (L2 ). The corresponding Gd3+ complexes possess one coordinated water molecule, as confirmed by luminescence lifetime measurements on the EuIII and TbIII analogues. A detailed 1 H and 17 O relaxometric characterization has revealed the parameters that govern the relaxivities of these complexes. The water-exchange rate of the mono-amide derivative GdL1 (kex 298 =1.52×106  s-1 ) is faster than that determined for the bis-amide complex GdL2 (kex 298 =0.73×106  s-1 ). 1 H and 19 F NMR studies have indicated that the complexes are present in solution almost exclusively as the square-antiprismatic (SAP) isomers. 19 F NMR relaxation studies indicated Gd⋅⋅⋅F distances of 7.4±0.1 and 9.1±0.1 Šfor GdL1 and GdL2 , respectively. Phantom MRI studies revealed the favorable properties of GdL2 as a dual 1 H/19 F magnetic resonance imaging (MRI) probe, whereas the shorter Gd⋅⋅⋅F distance of GdL1 reduces the signal-to-noise ratio due to the very short transverse relaxation time of the 19 F NMR signal.

A pentadentate member of the picolinate family for Mn(ii) complexation and an amphiphilic derivative.

We report a pentadentate ligand containing a 2,2'-azanediyldiacetic acid moiety functionalized with a picolinate group at the nitrogen atom (H3paada), as well as a lipophylic derivative functionalized with a dodecyloxy group at position 4 of the pyridyl ring (H3C12Opaada). The protonation constants of the paada3- ligand and the stability constant of the Mn(ii) complex were determined using a combination of potentiometric and spectrophotometric titrations (25 °C, 0.15 M NaCl). A detailed relaxometric characterisation was accomplished by recording 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and 17O chemical shifts and relaxation rates. These studies provide detailed information on the microscopic parameters that control their efficiency as relaxation agents in vitro. For the sake of completeness and to facilitate comparison, we also characterised the related [Mn(nta)]- complex (nta = nitrilotriacetate). Both the [Mn(paada)]- and [Mn(nta)]- complexes turned out to contain two inner-sphere water molecules in aqueous solution. The exchange rate of these coordinated water molecules was slower in [Mn(paada)]- (k298ex = 90 × 107 s-1) than in [Mn(nta)]- (k298ex = 280 × 107 s-1). The complexes were also characterised using both DFT (TPSSh/def2-TZVP) and ab initio CAS(5,5) calculations. The lipophylic [Mn(C12Opaada)]- complex forms micelles in solution characterised by a critical micellar concentration (cmc) of 0.31 ± 0.01 mM. This complex also forms a rather strong adduct with Bovine Serum Albumin (BSA) with an association constant of 5.5 × 104 M-1 at 25 °C. The enthalpy and entropy changes obtained for the formation of the adduct indicate that the binding event is driven by hydrophobic interactions.

On the consequences of the stereochemical activity of the Bi(iii) 6s2 lone pair in cyclen-based complexes. The [Bi(DO3A)] case.

We report a detailed study of the structure of the [Bi(DO3A)] complex both in the solid state and in solution. The X-ray crystal structure of [Bi(DO3A)] evidences the octa-coordination of the Bi(iii) ion, which is directly coordinated to the four nitrogen atoms of the cyclen unit and three oxygen atoms of the carboxylate groups. The octa-coordination is completed by an oxygen atom of a neighboring carboxylate group, which bridges Bi(iii) ions thanks to µ2-η1:η1 coordination, resulting in the formation of a coordination polymer. The Bi(iii) ion presents a twisted-square antiprismatic (TSAP) coordination geometry associated with the Δ(δδδδ)/Λ(λλλλ) enantiomeric pair. A computational DFT study indicates that the 6s2 lone pair of Bi(iii) is stereochemically active in [Bi(DO3A)] and most of the cyclen-based complexes reported in the literature. Depending on the spatial arrangement of the donor atoms of the ligand the lone pair points in different directions, so that Bi(iii) can easily accommodate different coordination environments. In solution the [Bi(DO3A)] complex exists as a monomeric complex, as demonstrated by DOSY measurements. The stability constant of the [Bi(DO3A)] complex, determined by using batch spectrophotometric titrations, was found to be rather high (log K = 26.85(5)). The complex presents characteristic absorption in the UV spectrum at 299 nm (ε = 8770 M-1 cm-1) that was attributed to the Bi(iii)-centered 6p ← 6s band on the basis of TDDFT calculations. Spectrophotometric titrations reveal weak binding of different anions to the [Bi(DO3A)] complex, with association constants of K11 = 3.55(8), 3.09(7), 6.2(1) and 2.19(5) for Cl-, Br-, I- and N3-, respectively.

Developing the family of picolinate ligands for Mn2+ complexation.

We have reported here a series of ligands containing pentadentate 6,6'-(azanediylbis(methylene))dipicolinic acid units that differ in the substituent present at the amine nitrogen atom (acetate: H3DPAAA; phenyl: H2DPAPhA; dodecyl: H2DPAC12A; 4-hexylphenyl: H2DPAC6PhA). The protonation constants of the hexadentate DPAAA3- and pentadentate DPAPhA2- ligands and the stability constants of their Mn2+ complexes were determined using pH-potentiometry (25 °C, 0.15 M NaCl). The mono-hydrated [Mn(DPAAA)]- complex (log KMnL = 13.19(5)) was found to be considerably more stable than the bis-hydrated [Mn(DPAPhA)] analogue (log KMnL = 9.55(1)). A detailed 1H and 17O NMR relaxometric study was carried out to determine the parameters that govern the proton relaxivities of these complexes. The [Mn(DPAC12A)] complex, which contains a dodecyl lipophilic chain, forms micelles in solution characterized by a critical micellar concentration (cmc) of 96(9) µM. The lipophilic [Mn(DPAC6PhA)] and [Mn(DPAC12A)] derivatives form rather strong adducts with Human Serum Albumin (HSA) with association constants of 7.1 ± 0.1 × 103 and 1.3 ± 0.4 × 105 M-1, respectively. The X-ray structure of the complex {K(H2O)4}{[Mn(DPAAA)(H2O)]}2 shows that the Mn2+ ion in [Mn(DPAAA)]- is coordinated to the six donor atoms of the ligand, a coordinated water molecule completing the pentagonal bipyramidal coordination environment.