Yb-to-Eu Cooperative Sensitization Upconversion in a Multifunctional Molecular Nonanuclear Lanthanide Cluster in Solution.

Lanthanide metal clusters excel in combining molecular and material chemistry properties. Here, we report an efficient cooperative sensitization UC phenomenon of a Eu3+/Yb3+ nonanuclear lanthanide cluster in CD3OD. The synthesis and characterization of the heteronuclear cluster in the solid state and solution are described together with the UC phenomenon showing Eu3+ luminescence in the visible region upon 980 nm NIR excitation of Yb3+ at concentrations as low as 100 nM. Alongside being the Eu/Yb cluster to display UC (with a quantum yield value of 4.88 × 10-8 upon 1.13 W cm-2 excitation at 980 nm), the cluster exhibits downshifted light emission of Yb3+ in the NIR region upon 578 nm visible excitation of Eu3+, which is ascribed to sensitization pathways for Yb through the 5D0 energy levels of Eu3+. Additionally, a faint emission is also observed at ca. 500 nm upon 980 nm excitation, originating from the cooperative luminescence of Yb3+. The [Eu8Yb(BA)16(OH)10]Cl cluster (BA = benzoylacetonate) is also a field-induced single-molecular magnet (SMM) under 4K with a modest Ueff/kB of 8.48 K, thereby joining the coveted list of Yb-SMMs and emerging as a prototype system for next-generation devices, combining luminescence with single-molecular magnetism in a molecular cluster.

Upconverting photons at the molecular scale with lanthanide complexes.

In this perspective, we summarise the major milestones to date in the field of molecular upconversion (UC) with lanthanide based coordination complexes. This begins from the leap firstly from solid-state to nanoparticular regimes, and further down the scale to the molecular domain. We explain the mechanistic intricacies of each differing way of generating upconverted photons, critiquing them and outlining our views on the benefits and limitations of each process, also offering our perspective and opinion on where these new molecular UC edifices will take us. This nascent area is already rapidly expanding and improving, having increased in luminance efficiency by more than four orders of magnitude in the last decade: we conclude that the future is bright for molecular UC.

Structural Variations in Carboxylated Bispidine Ligands: Influence of Positional Isomerism and Rigidity on the Conformation, Stability, Inertness and Relaxivity of their Mn2+ Complexes.

Mn2+ complexes of 2,4-pyridyl-disubstituted bispidine ligands have emerged as more biocompatible alternatives to Gd3+ -based MRI probes. They display relaxivities comparable to that of commercial contrast agents and high kinetic inertness, unprecedented for Mn2+ complexes. The chemical structure, in particular the substituents on the two macrocyclic nitrogens N3 and N7, are decisive for the conformation of the Mn2+ complexes, and this will in turn determine their thermodynamic, kinetic and relaxation properties. We describe the synthesis of four ligands with acetate substituents in positions N3, N7 or both. We evidence that the bispidine conformation is dependent on N3 substitution, with direct impact on the thermodynamic stability, kinetic inertness, hydration state and relaxivity of the Mn2+ complexes. These results unambiguously show that (i) solely a chair-chair conformation allows for favorable inertness and relaxivity, and (ii) in this family such chair-chair conformation is accessible only for ligands without N3-appended carboxylates.

55/52Mn2+ Complexes with a Bispidine-Phosphonate Ligand: High Kinetic Inertness for Imaging Applications.

Bispidine (3,7-diazabicyclo[3.3.1]nonane) provides a rigid and preorganized scaffold that is particularly interesting for the stable and inert complexation of metal ions, especially for their application in medical imaging. In this study, we present the synthesis of two bispidine ligands with N-methanephosphonate (H4L1) and N-methanecarboxylate (H3L2) substituents as well as the physico-chemical properties of the corresponding Mn2+ and Zn2+ complexes. The two complexes [Mn(L1)]2- and [Mn(L2)]- have relatively moderate thermodynamic stability constants according to potentiometric titration data. However, they both display an exceptional kinetic inertness, as assessed by transmetallation experiments in the presence of 50 equiv excess of Zn2+, showing only ∼40 and 20% of dissociation for [Mn(L1)]2- and [Mn(L2)]-, respectively, after 150 days at pH 6 and 37 °C. Proton relaxivities amount to r1 = 4.31 mM-1 s-1 ([Mn(L1)]2-) and 3.64 mM-1 s-1 ([Mn(L2)]-) at 20 MHz, 25 °C, and are remarkable for Mn2+ complexes with one inner-sphere water molecule (q = 1); they are comparable to that of the commercial contrast agent [Gd(DOTA)(H2O)]-. The presence of one inner-sphere water molecule and an associative water exchange mechanism was confirmed by temperature-dependent transverse 17O relaxation rate measurements, which yielded kex298 = 0.12 × 107 and 5.5 × 107 s-1 for the water exchange rate of the phosphonate and the carboxylate complex, respectively. In addition, radiolabeling experiments with 52Mn were also performed with H2(L1)2- showing excellent radiolabeling properties and quantitative complexation at pH 7 in 15 min at room temperature as well as excellent stability of the complex in various biological media over 24 h.

From Mono- to Polynuclear Coordination Complexes with a 2,2'-Bipyrimidine-4,4'-dicarboxylate Ligand.

The coordination properties of the ligand 2,2'-bipyrimidine-4,4'-dicarboxylic acid (H2bpd) with lanthanide(III) ions (Ln = Eu, Tb, or Lu) were investigated. The syntheses of the H2bpd ligand and its salts, [K2(bpd)(H2O)2] (1) and [(AlkNH)Lu(bpd)2] (Alk = Et, Hex, or en), are described. In the presence of LnCl3 salts (Ln = Lu, Eu, or Tb), the formation of [Ln(bpd)2]- and [Ln(bpd)(H2O)x]+ species was assessed by 1H nuclear magnetic resonance (NMR), spectrophotometry, and spectrofluorometric titrations in aqueous solution. The solid state structure of 1, [K(H2O)2][Lu(bpd)2] (2), and [(Et3NH)Lu(bpd)2] (3) could be determined by X-ray diffraction, showing the ligand to act as a tetradentate unit with formation of three five-membered chelate rings around the central Ln(III). With the aim of building polynuclear assemblies, the coordination between [Lu(bdp)2]- and [Lu(tta)3(H2O)] units (tta = thenoyltrifluoroacetylacetonate) was also investigated. In methanol, 1H NMR titration experiments revealed the formation of complex mixtures from which two new species could be identified, [Lu2(bpd)(tta)4] (4) and H[Lu(bpd)(tta)2] (5), as confirmed by their solid state structure analysis. Using highly lipophilic cations in chloroform, the octametallic complex [enH]4[Lu8(bpd)4(tta)18] (6) could be isolated and its X-ray structure determined.

Optical spin-state polarization in a binuclear europium complex towards molecule-based coherent light-spin interfaces.

The success of the emerging field of solid-state optical quantum information processing (QIP) critically depends on the access to resonant optical materials. Rare-earth ion (REI)-based molecular systems, whose quantum properties could be tuned taking advantage of molecular engineering strategies, are one of the systems actively pursued for the implementation of QIP schemes. Herein, we demonstrate the efficient polarization of ground-state nuclear spins-a fundamental requirement for all-optical spin initialization and addressing-in a binuclear Eu(III) complex, featuring inhomogeneously broadened 5D0 → 7F0 optical transition. At 1.4 K, long-lived spectral holes have been burnt in the transition: homogeneous linewidth (Γh) = 22 ± 1 MHz, which translates as optical coherence lifetime (T2opt) = 14.5 ± 0.7 ns, and ground-state spin population lifetime (T1spin) = 1.6 ± 0.4 s have been obtained. The results presented in this study could be a progressive step towards the realization of molecule-based coherent light-spin QIP interfaces.

Formation of Heteropolynuclear Lanthanide Complexes Using Macrocyclic Phosphonated Cyclam-Based Ligands.

Ligands L1 and L2, respectively based on a cyclam and a cross-bridged cyclam scaffold functionalized at N1 and N8 by 6-phosphonic-2-methylene pyridyl groups, are described. While complexation of lanthanide (Ln) cations with L2 was not possible, a family of complexes has been prepared with L1, of the general formulae [LnL1H2]Cl (Ln3+ = Lu, Tb, Yb) or [LnL1H] (Ln3+ = Eu). The solution, structural, potentiometric, and photophysical data for these novel ligands and their complexes have been investigated, including a solid-state study by X-ray diffraction (L1, L2, and [EuL1H]), 1H NMR complexation investigations (Lu3+), as well as UV-vis absorption and luminescence spectroscopy in water and D2O (pH ≈ 7). L1 forms 1:1 metal-ligand stoichiometric octadentate complexes in solution. Importantly, the pyridyl phosphonate functions are capable of simultaneous chelation to the metal center and of interaction with a second metal center. 1H NMR (Lu3+) and spectrophotometric titrations of the isolated [TbL1]- complex by EuCl3 salts demonstrated the formation of high-order (hetero)polymetallic species in aqueous solution (H2O, pH = 7). Global analysis of the luminescence titration experiment points to the formation of 4:1, 3:1, and 3:2 [TbL1]/Eu heteropolynuclear assemblies, exhibiting a strong preference to forming [TbL1]3Eu2 at increased europium concentrations, with energy transfer occurring between the kinetically inert terbium complex and added europium cations.

Ultrabright Terbium Nanoparticles for FRET Biosensing and in Situ Imaging of Epidermal Growth Factor Receptors*.

Lanthanide-doped nanoparticles (LnNPs) have become an important class of fluorophores for advanced biosensing and bioimaging. LnNPs that are photosensitized by surface-attached antenna ligands can possess exceptional brightness. However, their functional bioconjugation remains an important challenge for their translation into bioanalytical applications. To solve this problem, we designed a ligand that can be simultaneously applied as efficient light harvesting antenna for Tb surface ions and strong linker of biomolecules to the LnNPs surfaces. To demonstrate generic applicability of the photosensitized TbNP-bioconjugates, we applied them in two prototypical applications for biosensing and bioimaging. First, in-solution biorecognition was shown by time-resolved Förster resonance energy transfer (FRET) between streptavidin-functionalized TbNPs to biotinylated dyes (ATTO 610). Second, in situ detection of ligand-receptor binding on cells was accomplished with TbNP-antibody (Matuzumab) conjugates that could specifically bind to transmembrane epidermal growth factor receptors (EGFR). High specificity and sensitivity were demonstrated by time-gated imaging of EGFR on both strongly (A431) and weakly (HeLa and Cos7) EGFR-expressing cell lines, whereas non-expressing cell lines (NIH3T3) and EGFR-passivated A431 cells did not show any signals. Despite the relatively large size of TbNP-antibody conjugates, they could be internalized by A431 cells upon binding to extracellular EGFR, which showed their potential as bright and stable luminescence markers for intracellular signaling.

Unprecedented Kinetic Inertness for a Mn2+ -Bispidine Chelate: A Novel Structural Entry for Mn2+ -Based Imaging Agents.

The search for more biocompatible alternatives to Gd3+ -based MRI agents, and the interest in 52 Mn for PET imaging call for ligands that form inert Mn2+ chelates. Given the labile nature of Mn2+ , high inertness is challenging to achieve. The strongly preorganized structure of the 2,4-pyridyl-disubstituted bispidol ligand L1 endows its Mn2+ complex with exceptional kinetic inertness. Indeed, MnL1 did not show any dissociation for 140 days in the presence of 50 equiv. of Zn2+ (37 °C, pH 6), while recently reported potential MRI agents MnPyC3A and MnPC2A-EA have dissociation half-lives of 0.285 h and 54.4 h under similar conditions. In addition, the relaxivity of MnL1 (4.28 mm-1 s-1 at 25 °C, 20 MHz) is remarkable for a monohydrated, small Mn2+ chelate. In vivo MRI experiments in mice and determination of the tissue Mn content evidence rapid renal clearance of MnL1 . Additionally, L1 could be radiolabeled with 52 Mn and the complex revealed good stability in biological media.

Evaluation of a Bispidine-Based Chelator for Gallium-68 and of the Porphyrin Conjugate as PET/PDT Theranostic Agent.

In this study a bispidine ligand has been applied to the complexation of gallium(III) and radiolabelled with gallium-68 for the first time. Despite its 5-coordinate nature, the resulting complex is stable in serum for over two hours, demonstrating a ligand system well matched to the imaging window of gallium-68 positron emission tomography (PET). To show the versatility of the bispidine ligand and its potential use in PET, the bifunctional chelator was conjugated to a porphyrin, producing a PET/PDT-theranostic, which showed the same level of stability to serum as the non-conjugated gallium-68 complex. The PET/PDT complex killed >90 % of HT-29 cells upon light irradiation at 50 µm. This study shows bispidines have the versatility to be used as a ligand system for gallium-68 in PET.

pH-Dependent Hydration Change in a Gd-Based MRI Contrast Agent with a Phosphonated Ligand.

The heptadentate ligand L was shown to form an extremely stable Gd complex at neutral pH with a pGd value of 18.4 at pH 7.4. The X-ray crystal structures of the complexes formed with Gd and Tb displayed two very different coordination behaviors being, respectively, octa- and nonacoordinated. The relaxometric properties of the Gd complex were studied by field-dependent relaxivity measurements at various temperatures and by 17 O NMR spectroscopy. The pH-dependence of the longitudinal relaxivity profile indicated large changes around neutral pH leading to a very large value of 10.1 mm-1 ⋅s-1 (60 MHz, 298 K) at pH 4.7. The changes were attributed to an increase of the hydration number from one water molecule in basic conditions to two at acidic pH. A similar trend was observed for the luminescence of the Eu complex, confirming the change in hydration state. DOSY experiments were performed on the Lu analogue, pointing to the absence of dimers in solution in the considered pH range. A breathing mode of the complex was postulated, which was further supported by 1 H and 31 P NMR spectroscopy of the Yb complex at varying pH and was finally modeled by DFT calculations.

2,4-Substituted bispidines as rigid hosts for versatile applications: from κ-opioid receptor to metal coordination.

Bispidones (3,7-diazabicyclo[3.3.1]nonan-9-one) are bicyclic analogues of the natural antiarrhythmic agent, spartein. They can straightforwardly be obtained from two successive Mannich reactions. Reduction of the ketone gives the corresponding bispidol. Substituted bispidones and bispidols offer a large playground by varying the substituents, the configuration of the carbon atoms in position 2 and 4 as well as the conformation of the bicycle. While chair-boat conformers display a strong affinity for κ-opioid receptors, chair-chair bispidines provide adaptable coordination spheres for transition metal and rare-earth ions. Because of their very rich coordination chemistry, substituted bispidines have emerged in various applications of coordination chemistry, such as catalysis, magnetism and medical imaging.

The role of ligand to metal charge-transfer states on the luminescence of Europium complexes with 18-membered macrocyclic ligands.

We report a detailed study of the photophysical properties of EuIII and TbIII complexes with two ligands based on a 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane platform containing either four pyridine-2yl-methyl (L1) or four hydroxyethyl (L2) pendant arms. The [TbL1]3+ and [TbL2]3+ complexes present moderate luminescence quantum yields upon excitation through the ligand bands (φH2O = 7.4 and 21%, respectively). The [EuL2]3+ complex displays a relatively low quantum yield in H2O (φH2O = 1.6%) that increases considerably in D2O (φD2O = 5.3%), which highlights the strong quenching effect of the four ligand O-H oscillators. The emission spectrum of [EuL1]3+ is rather unusual in that it shows a relatively high intensity of the 5D0 → 7F5,6 transitions, which appears to be also related to the distorted D4d symmetry of the coordination polyhedron. Surprisingly, the quantum yield of the [EuL1]3+ complex is very low (φH2O = 0.10%), considering the good protection of the EuIII coordination environment offered by the ligand. Cyclic voltammograms recorded from aqueous solutions of [EuL1]3+ display a reversible curve with a half-wave potential of -620 mV (versus Ag/AgCl), while [EuL2]3+ presents a reduction peak at more negative potential (-1040 mV). Thus, the L1 ligand provides a rather good stabilisation of divalent Eu compared to the L2 analogue, suggesting that the presence of a low-lying ligand-to-metal charge-transfer (LMCT) state might be responsible for the low quantum yield determined for [EuL1]3+. A density functional theory (DFT) study provides very similar energies for the ligand-centered excited singlet (1ππ*) and triplet (3ππ*) states of [EuL1]3+ and [EuL2]3+. The energy of the 9LMCT state of [EuL1]3+ was estimated to be 20 760 cm-1 by using all-electron relativistic calculations based on the DKH2 approach, a value that decreases to 15 940 cm-1 upon geometry relaxation.

Molecular Upconversion in Water in Heteropolynuclear Supramolecular Tb/Yb Assemblies.

Piling up excited states to reach upconversion (UC) is severely restricted by vibrational quenching mechanisms, especially when one looks at discrete molecular entities in solution. By carefully controlling the supramolecular assembly processes resulting from the strong electrostatic interactions between negatively charged Yb complexes and Tb3+ cations in aqueous solutions, we engineered the formation of heteropolynuclear complexes of [(YbL)2Tb x] compositions ( x = 1 and 2). These edifices display a phenomenon of cooperative photosensitization UC with green emission of the Tb cations upon NIR excitation at 980 nm in the Yb absorption band. The photophysical properties of the complexes were carefully investigated by steady-state and time-resolved luminescence experiments in D2O, allowing one to quantify the impact of the composition and pD of the solution on the emission intensity as well as clarifying the exact cooperative photosensitization upconversion mechanism. Using optimized conditions, the energy transfer UC process could be observed for the first time in nondeuterated water with discrete molecular compounds.

Sensing Uranyl(VI) Ions by Coordination and Energy Transfer to a Luminescent Europium(III) Complex.

The release of uranyl(VI) is a hazardous environmental issue, with limited ways to monitor accumulation in situ. Here, we present a method for the detection of uranyl(VI) ions through the utilization of a unique fluorescence energy transfer process to europium(III). Our system displays the first example of a "turn-on" europium(III) emission process with a small, water-soluble lanthanide complex triggered by uranyl(VI) ions.

Formation of Mono- and Polynuclear Luminescent Lanthanide Complexes based on the Coordination of Preorganized Phosphonated Pyridines.

A series of polynuclear assemblies based on ligand L (1,4,7-tris[hydrogen (6-methylpyridin-2-yl)phosphonate]-1,4,7-triazacyclononane) has been developed. The coordination properties of ligand L with LnIII (Ln = La, Eu, Tb, Yb, Lu) have been studied in water (pH = 7.0) and in D2O (pD = 7.0) by UV-absorption spectrometry, spectrofluorimetry, 1H and 31P NMR, DOSY, ESI-mass spectrometry, and X-ray diffraction. This nonadentate ligand forms highly stable mononuclear complexes in water and provides a very efficient shielding of the Ln cations, as emphasized by the very good luminescence properties of the Yb complex in D2O, especially regarding its lifetime (τD2O = 10.2 µs) and quantum yield (ϕD2O = 0.42%). In the presence of excess LnIII cation, polynuclar complexes of [(LnL)2Ln x] stoichiometry (x = 1 and x = 2) are observed in solution. In the solid state, a dinuclear complex of La could be isolated and structurally characterized by X-ray diffraction, unraveling the presence of strong hydrogen bonding interactions between a La(H2O)93+ cation and the [LaL]3- complex.

Energy Transfer in Supramolecular Heteronuclear Lanthanide Dimers and Application to Fluoride Sensing in Water.

In the presence of fluoride anions, [LnL(H2 O)]+ complexes, based on the coordination of a lanthanide (Ln) cation into the cavity of a C2v symmetrical cyclen-based ligand (L), self-assemble in water to form [(LnL)2 F]+ dimers. The crystal structures of the Yb hydrated monomer and of the fluorinated dimer are reported and analyzed to unravel the impact of the cumulative effect of weak hydrogen bonding and aromatic stacking interactions in the supramolecular assembly. The assembly is stable over a broad range of pH 3-8. A combination of equimolar amounts of Eu and Tb complexes led to a quasistatistical mixture of homo- and heterodimers, as observed by using electrospray mass spectrometry. In the heterodimers, selective excitation into the 7 F6 →5 D4 absorption band of the Tb center at λ=488 nm allowed the observation of a Tb-to-Eu downshifting energy transfer, not observed in the absence of fluoride ions. Analysis of the excited-state lifetimes of the dimers within the frame of the Förster theory of energy transfer showed the transfer to have an efficiency of 34 %, with a corresponding Förster radius of 4.1 Å; thereby, unraveling the short Ln-Ln distance as a crucial parameter of the energy-transfer process. By using equimolar mixtures of the Tb and Eu complexes, the energy-transfer phenomenon was used for a ratiometric sensing of fluoride anions in water with a detection limit of 17.7 nm.

A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and 64Cu Labeling.

Here we present the synthesis and characterization of a new bispidine (3,7-diazabicyclo[3.3.1]nonane) ligand with N-methanephosphonate substituents (L2). Its physicochemical properties in water, as well as those of the corresponding Cu(II) and Zn(II) complexes, have been evaluated by using UV-visible absorption spectroscopy, potentiometry, 1H and 31P NMR, and cyclic voltammetry. Radiolabeling experiments with 64CuII have been carried out, showing excellent radiolabeling properties. Quantitative complexation was achieved within 60 min under stoichiometric conditions, at room temperature and in the nanomolar concentration range. It was also demonstrated that the complexation occurred below pH 2. Properties have been compared to those of the analogue bispidol bearing a N-methanecarboxylate substituent (L1). Although both systems meet the required criteria to be used as new chelator for 64/67Cu in terms of the kinetics of formation, thermodynamic stability, selectivity for Cu(II), and kinetic inertness regarding redox- or acid-assisted decomplexation processes, substitution of the carboxylic acid function by the phosphonic moiety is responsible for a significant increase in the thermodynamic stability of the Cu(II) complex (+2 log units for pCu) and also leads to an increase in the radiochemical yields with 64CuII which is quantitative for L2.

Upconverted Photosensitization of Tb Visible Emission by NIR Yb Excitation in Discrete Supramolecular Heteropolynuclear Complexes.

Addition of Tb3+ salts to a solution of a (YbLD) complex in D2O resulted in the formation of [(YbLD)2Tbx] (x = 1 to 3) complexes that, upon NIR excitation at 980 nm, showed an unprecedented Yb to Tb upconversion sensitization phenomenon resulting in the observation of the typical green emission of Tb.

Bifunctional bispidine derivatives for copper-64 labelling and positron emission tomography.

The first radiolabelling studies of a bispidine (3,7-diazabicyclo[3.3.1]nonane) derivative substituted by a glycinate pendant arm (L1) with 64Cu are reported. Labelling was fast and easily performed at room temperature and in a wide range of pH values. Under these conditions, radiochemical yields over 90% were achieved within 5 minutes at micromolar concentration of the ligand. A bifunctional analogue of L1 (L2) has been obtained by introducing an l-lysine amino acid on the bispidine skeleton. Ligand L2 demonstrates good radiolabelling capacities at room temperature and in water (pH 4 to pH 6). This new bispidine is a versatile platform which can easily react with NHS esters and can be subsequently coupled to a recognition unit in order to perform targeted Positron Emission Tomography (PET) imaging. As a proof of concept, two new bifunctional chelators (BFCs) with a biotin (L3) or a maleimide functional group (L4) have been synthesized. The biotinylated BFC is very valuable for pretargeting strategies using streptavidin-conjugated antibodies. The reactivity of the maleimide derivative L4 has been studied with the model peptide GP120. Quantitative coupling has been achieved under physiological conditions, showing a good regioselectivity towards cysteine residues versus lysine amino acids.