Sensitization of Europium Oxide Nanoparticles Enhances Signal-to-Noise over Autofluorescence with Time-Gated Luminescence Detection.

Clinical translation of nanoparticle-based therapeutics has been limited, and a lack of preclinical delivery characterization is partly to blame, limiting our understanding of the mechanisms of failure. The improvement of the preclinical delivery assessment requires nanoparticles with higher detectability. This work focused on the exploration of several aromatic carboxylic ligands (terephthalic acid, quinaldic acid, and kynurenic acid) for the sensitization of europium oxide nanoparticles with a long emission lifetime to overcome cellular autofluorescence, a key confounder of detection in luminescence-based bioimaging. A facile one-pot synthesis and ligand exchange process generated and sensitized ultrasmall Eu2O3 cores. As reflected in the emission spectra and lifetimes, ligand binding yielded unique coordination environments around Eu3+. Then, the efficacy of sensitization was tested against the autofluorescence provided by tissue lysate. Normal (simultaneous excite-read) measurements showed integrated signal improvements over autofluorescence of 2.2-, 3.9-, and 14.0-fold for EuTA, EuQA, and EuKA, respectively. In time-gated mode, the improvements over autofluorescence were more dramatic with fold differences of 75-, 89-, and 108-fold for EuTA, EuQA, and EuKA, respectively. The investigation of novel sensitizers expands the breadth of the field of sensitized lanthanide oxide nanoparticles, and the signal enhancement observed with sensitization and time-gating supports the utility of the generated samples for future bioimaging applications.

Solution Structures of Europium Terpyridyl Complexes with Nitrate and Triflate Counterions in Acetonitrile.

Lanthanide-ligand complexes are key components of technological applications, and their properties depend on their structures in the solution phase, which are challenging to resolve experimentally or computationally. The coordination structure of the Eu3+ ion in different coordination environments in acetonitrile is examined using ab initio molecular dynamics (AIMD) simulations and extended X-ray absorption fine structure (EXAFS) spectroscopy. AIMD simulations are conducted for the solvated Eu3+ ion in acetonitrile, both with or without a terpyridyl ligand, and in the presence of either triflate or nitrate counterions. EXAFS spectra are calculated directly from AIMD simulations and then compared to experimentally measured EXAFS spectra. In acetonitrile solution, both nitrate and triflate anions are shown to coordinate directly to the Eu3+ ion forming either ten- or eight-coordinate solvent complexes where the counterions are binding as bidentate or monodentate structures, respectively. Coordination of a terpyridyl ligand to the Eu3+ ion limits the available binding sites for the solvent and anions. In certain cases, the terpyridyl ligand excludes any solvent binding and limits the number of coordinated anions. The solution structure of the Eu-terpyridyl complex with nitrate counterions is shown to have a similar arrangement of Eu3+ coordinating molecules as the crystal structure. This study illustrates how a combination of AIMD and EXAFS can be used to determine how ligands, solvent, and counterions coordinate with the lanthanide ions in solution.

Lanthanide Luminescence and Thermochromic Emission from Soft-Atom Donor Dichalcogenoimidodiphosphinate Ligands.

The luminescence properties of two divalent europium complexes of the type Eu[N(SPPh2)2]2(THF)2 (1) and Eu[N(SePPh2)2]2(THF)2 (2) were investigated. The first complex, Eu[N(SPPh2)2]2(THF)2 (1), was found to be isomorphous with the reported structure of complex 2 and exhibited room temperature luminescence with thermochromic emission upon cooling. We found the complex Eu[N(SePPh2)2]2(THF)2 (2) was also thermochromic but the emission intensity was sensitive to temperature. Both room temperature and low temperature (100 K) single crystal X-ray structural investigation of 1 and 2 indicate geometric distortions of the metal coordination, which may be important for understanding the thermochromic behavior of these complexes. The trivalent europium complex Eu[N(SPPh2)2]3 (3) with the same ligand as 1 was also structurally characterized as a function of temperature and exhibited temperature-dependent luminescence intensity, with no observable emission at room temperature but intense luminescence at 77 K. Variable temperature Raman spectroscopy was used to determine the onset temperature of luminescence of Eu[N(SPPh2)2]3 (3), where the 615 nm (5D0 → 7F2 transition) peak was quenched above 130 K. The UV-visible diffuse reflectance of 3 provides evidence of an LMCT band, supporting a mechanism of thermally activated LMCT quenching of Eu(III) emitting states. A series of ten isomorphous, trivalent lanthanide complexes of type Ln[N(SPPh2)2]3 (Ln = Eu (3) Pr (4), Nd (5), Sm (6), Gd (7), Tb (8)) and Ln[N(SePPh2)2]3 (Ln = Pr (9), Nd (10, structure was previously reported), Sm (11), and Gd (12) for Q = Se) were also synthesized and structurally characterized. These complexes for Ln = Pr, Nd, Sm, and Tb exhibited room temperature luminescence. This study provides examples of temperature-dependent luminescence of both Eu2+ and Eu3+, and the use of soft-atom donor ligands to sensitize lanthanide luminescence in a range of trivalent lanthanides, spanning near IR and visible emitters.

Carbazole-Functionalized Dipicolinato LnIII Complexes Show Two-Photon Excitation and Viscosity-Sensitive Metal-Centered Emission.

EuIII and YbIII complexes with the carbazole-dipicolinato ligand dpaCbz2-, namely K3[Eu(dpaCbz)3] and K3[Yb(dpaCbz)3], were isolated. The EuIII complex displayed metal-centred emission upon one-photon excitation with a sensitized emission efficiency Φ L Ln of 1.8±0.3 %, corresponding to an intrinsic emission efficiency Φ Ln Ln of 46% and a sensitization efficiency of ηsens 3.9%, with an emission lifetime of the emissive state τ of 1.087±0.005 ms. The YbIII complex displayed Φ L Ln of 0.010±0.001 %, and a τ of 2.32±0.06 µs. The EuIII-centred emission was sensitized as well upon two-photon excitation and a two-photon absorption cross-section σ2PA of 63 GM at 750 nm was determined for the complex. The one- or two-photon sensitized emission intensity of the EuIII complex changes by more than two-fold when the solvent viscosity is varied in the range 0.5 - 200 cP and the emission is independent of dissolved oxygen. The YbIII complex displays a change in emission intensity as well. However, in this case, a dependence of the emission intensity on dissolved oxygen content was observed.

Photocytotoxicity of Thiophene- and Bithiophene-Dipicolinato Luminescent Lanthanide Complexes.

New thiophene-dipicolinato-based compounds, K2nTdpa (n = 1, 2), were isolated. Their anions are sensitizers of lanthanide ion (LnIII) luminescence and singlet oxygen generation (1O2). Emission in the visible and near-infrared regions was observed for the LnIII complexes with efficiencies (ϕLn) ϕEu = 33% and ϕYb = 0.31% for 1Tdpa2- and ϕYb = 0.07% for 2Tdpa2-. The latter does not sensitize EuIII emission. Fluorescence imaging of HeLa live cells incubated with K3[Eu(1Tdpa)3] indicates that the complex permeates the cell membrane and localizes in the mitochondria. All complexes generate 1O2 in solution with efficiencies (ϕO12) as high as 13 and 23% for the GdIII complexes of 1Tdpa2- and 2Tdpa2-, respectively. [Ln(nTdpa)3]3- (n = 1, 2) are phototoxic to HeLa cells when irradiated with UV light with IC50 values as low as 4.2 µM for [Gd(2Tdpa)3]3- and 91.8 µM for [Eu(1Tdpa)3]3-. Flow cytometric analyses indicate both apoptotic and necrotic cell death pathways.

New up-conversion luminescence in molecular cyano-substituted naphthylsalophen lanthanide(iii) complexes.

A new naphthylsalophen and its 3 : 2 ligand-to-lanthanide sandwich-type complexes were isolated. When excited at 380 nm, the complexes display the characteristic metal-centred emission for NdIII, ErIII and YbIII. Upon 980 nm excitation, in mixed lanthanide and the Er complexes, Er-centred upconversion emission at 543 and 656 nm is observed, with power densities as low as 2.18 W cm-2.

Solution structure of a europium-nicotianamine complex supports that phytosiderophores bind lanthanides.

We report the solution structure of a europium-nicotianamine complex predicted from ab initio molecular dynamics simulations with density functional theory. Emission and excitation spectroscopy show that the Eu3+ coordination environment changes in the presence of nicotianamine, suggesting complex formation, such as what is seen for the Eu3+-nicotianamine complex structure predicted from computation. We modeled Eu3+-ligand complexes with explicit water molecules in periodic boxes, effectively simulating the solution phase. Our simulations consider possible chemical events (e.g. coordination bond formation, protonation state changes, charge transfers), as well as ligand flexibility and solvent rearrangements. Our computational approach correctly predicts the solution structure of a Eu3+-ethylenediaminetetraacetic acid complex within 0.05 Å of experimentally measured values, backing the fidelity of the predicted solution structure of the Eu3+-nicotianamine complex. Emission and excitation spectroscopy measurements were also performed on the well-known Eu3+-ethylenediaminetetraacetic acid complex to validate our experimental methods. The electronic structure of the Eu3+-nicotianamine complex is analyzed to describe the complexes in greater detail. Nicotianamine is a metabolic precursor of, and structurally very similar to, phytosiderophores, which are responsible for the uptake of metals in plants. Although knowledge that nicotianamine binds europium does not determine how plants uptake rare earths from the environment, it strongly supports that phytosiderophores bind lanthanides.

Full Visible Spectrum and White Light Emission with a Single, Input-Tunable Organic Fluorophore.

The blue emission of M2biQ can be tuned to specific wavelengths throughout the visible region by changing the identity of the cation it interacts with. These optical properties are observed in MeCN solution and the solid state. White light is obtained in MeCN by using either the proper ratio of zinc ions or acid. Thus, M2biQ acts as a nearly universal emitter (λem = 468-690 nm) with large Stokes shifts (116-306 nm, Δν̃ = 7,042-11,823 cm-1). Full spectral profiles as well as quantum yields, lifetimes, and the crystal structures of key RGB and yellow emitters are reported. Emission wavelengths correlate with cationic radius, and TD-DFT calculations show that, for 1:1 complexes, the smaller the ion, the shorter the N-cation bond, and the greater the bathochromic emission shift.

Effect of the aromatic substituent on the para-position of pyridine-bis(oxazoline) sensitizers on the emission efficiency of their EuIII and TbIII complexes.

Two efficient lanthanide ion sensitizers 2,6-bis(oxazoline)-4-phenyl-pyridine (PyboxPh, 1) and 2,6-bis(oxazoline)-4-thiophen-2-yl-pyridine (Pybox2Th, 2) were synthesized. 1 crystallizes in the monoclinic space group P21/c with cell parameters a = 16.3794(4) Å, b = 7.2856(2) Å, c = 11.7073(3) Å, ß = 97.229(1)° and V = 1385.97(6) Å3. 2 crystallizes in the monoclinic space group P21/n with cell parameters a = 5.9472(2), b = 16.0747(6), c = 14.3716(5) Å, ß = 93.503(1)° and V = 1371.35(8) Å3. Photophysical characterization of 1 shows that its triplet state energy is located at 22 250 cm-1 and efficient energy transfer is observed for EuIII and TbIII. Solutions of [Ln(PyboxPh)3]3+ in dichloromethane display an emission efficiency of 37.2% for Ln[double bond, length as m-dash]Eu and 24.0% for Ln[double bond, length as m-dash]Tb. The excited state lifetimes for EuIII and TbIII are 2.227 ms and 723 µs, respectively. The triplet state energy of 2 is located at 19 280 cm-1 and is therefore too low to efficiently sensitize TbIII emission. However, the sensitization of EuIII is effective, with an emission quantum yield of 14.5% and an excited state lifetime of 714 µs. This shows that the derivatization of the chelator is strongly influenced by the aromatic substituents on the para-position of the pyridine ring. New isostructural 1 : 1 complexes of PyboxPh with EuIII (3) and TbIII (4) were also isolated and crystallize in the triclinic space group P1[combining macron] with cell parameters a = 9.1845(2) Å, b = 10.3327(2) Å, c = 11.9654(2) Å, α = 98.419(1)°, ß = 108.109(1)°, γ = 91.791(1)°, V = 1064.08(4) Å3 and a = 7.8052(1) Å, b = 11.8910(1) Å, c = 14.2668(2) Å, α = 72.557(1)°, ß = 86.355(1)°, γ = 77.223(1)°, V = 1231.95(3) Å3, respectively.

Luminescence of Lanthanide Complexes with Perfluorinated Alkoxide Ligands.

Four groups of rare-earth complexes, comprising 11 new compounds, with fluorinated O-donor ligands ([K(THF)6][Ln(OC4F9)4(THF)2] (1-Ln; Ln = Ce, Nd), [K](THF)x[Ln(OC4F9)4(THF)y] (2-Ln; Ln = Eu, Gd, Dy), [K(THF)2][Ln(pinF)2(THF)3] (3-Ln; Ln = Ce, Nd), and [K(THF)2][Ln(pinF)2(THF)2] (4-Ln; Ln = Eu, Gd, Dy, Y) have been synthesized and characterized. Single-crystal X-ray diffraction data were collected for all compounds except 2-Ln. Species 1-Ln, 3-Ln, and 4-Ln are uncommon examples of six-coordinate (Eu, Gd, Dy, and Y) and seven-coordinate (Ce and Nd) LnIII centers in all-O-donor environments. Species 1-Ln, 2-Ln, 3-Ln, and 4-Ln are all luminescent (except where Ln = Gd and Y), with the solid-state emission of 1-Ce being exceptionally blue-shifted for a Ce complex. The emission spectra of the six Nd, Eu, and Dy complexes do not show large differences based on the ligand and are generally consistent with the well-known free-ion spectra. Time-dependent density functional theory results show that 1-Ce and 3-Ce undergo allowed 5f → 4d excitations, consistent with luminescence lifetime measurements in the nanosecond range. Eu-containing 2-Eu and 4-Eu, however, were found to have luminescence lifetimes in the millisecond range, indicating phosphorescence rather than fluorescence. The performance of a pair of multireference models for prediction of the Ln = Nd, Eu, and Dy absorption spectra was assessed. It was found that spectroscopy-oriented configuration interaction as applied to a simplified model in which the free-ion lanthanide was embedded in ligand-centered Löwdin point charges performed as well (Nd) or better (Eu and Dy) than canonical NEVPT2 calculations, when the ligand orbitals were included in the treatment.

Luminescent lanthanide complexes with a pyridine-bis(carboxamide)-bithiophene sensitizer showing wavelength-dependent singlet oxygen generation.

A new pyridine-bis(carboxamide)-based ligand with a bithiophene pendant, 2Tcbx, was synthesized. Its lanthanide ion (LnIII) complexes, [Ln(2Tcbx)2]3+, were isolated and their photophysical properties were explored. Upon excitation at 360 nm, these complexes display emission in the near-infrared (NIR) with efficiencies of 0.69% for LnIII = YbIII, 0.20% for LnIII = NdIII, and 0.01% for LnIII = ErIII, respectively. Concurrent 1O2 formation was seen for all complexes, with efficiencies of 19% for the YbIII complex, 25% for the NdIII complex, and 9% for the ErIII complex. When exciting at a longer wavelength, 435 nm, only LnIII emission was observed and larger efficiencies of LnIII-centered emission were obtained. The lack of 1O2 generation indicates that energy pathways involving different ligand conformations, which were investigated by transient absorption spectroscopy, are involved in the sensitization process, and enable the wavelength-dependent generation of 1O2.

Photocytotoxicity of Oligothienyl-Functionalized Chelates That Sensitize LnIII Luminescence and Generate 1 O2.

Three new compounds containing a heptadentate lanthanide (LnIII ) ion chelator functionalized with oligothiophenes, nThept(COOH)4 (n=1, 2, or 3), were isolated. Their LnIII complexes not only display the characteristic metal-centered emission in the visible or near-infrared (NIR) but also generate singlet oxygen (1 O2 ). Luminescence efficiencies (ϕLn ) for [Eu1Thept(COO)4 ]- and [Eu2Thept(COO)4 ]- are ϕEu =3 % and 0.5 % in TRIS buffer and 33 % and 3 % in 95 % ethanol, respectively. 3Thept(COO)4 4- does not sensitize EuIII emission due to its low-lying triplet state. Near infra-red (NIR) luminescence is observed for all NIR-emitting LnIII and ligands with efficiencies of ϕYb =0.002 %, 0.005 % and 0.04 % for [YbnThept(COO)4 ]- (n=1, 2, or 3), and ϕNd =0.0007 %, 0.002 % and 0.02 % for [NdnThept(COO)4 ]- (n=1, 2, or 3) in TRIS buffer. In 95 % ethanol, quantum yields of NIR luminescence increase and are ϕYb =0.5 %, 0.31 % and 0.05 % for [YbnThept(COO)4 ]- (n=1, 2, or 3), and ϕNd =0.40 %, 0.45 % and 0.12 % for [NdnThept(COO)4 ]- (n=1, 2, or 3). All complexes are capable of generating 1 O2 in 95 % ethanol with ϕ1Ο2 efficiencies which range from 2 % to 29 %. These complexes are toxic to HeLa cells when irradiated with UV light (λexc =365 nm) for two minutes. IC50 values for the LnIII complexes are in the range 15.2-16.2 µm; the most potent compound is [Nd2Thept(COO)4 ]- . The cell death mechanisms are further explored using an Annexin V-propidium iodide assay which suggests that cell death occurs through both apoptosis and necrosis.

Wavelength-Dependent Singlet Oxygen Generation in Luminescent Lanthanide Complexes with a Pyridine-Bis(Carboxamide)-Terthiophene Sensitizer.

Lanthanide ion (LnIII ) complexes, [Ln(3Tcbx)2 ]3+ (LnIII =YbIII , NdIII , ErIII ) are isolated with a new pyridine-bis(carboxamide)-based ligand with a 2,2':5',2''-terthiophene pendant (3TCbx), and their resulting photophysical properties are explored. Upon excitation of the complexes at 490 nm, only LnIII emission is observed with efficiencies of 0.29 % at 976 nm for LnIII =YbIII and 0.16 % at 1053 nm for LnIII =NdIII . ErIII emission is observed but weak. Upon excitation at 400 nm, concurrent 1 O2 formation is seen, with efficiencies of 11 % for the YbIII and NdIII complexes and 13 % for the ErIII complex. Owing to the concurrent generation of 1 O2 , as expected, the efficiency of metal-centered emission decreases to 0.02 % for YbIII and 0.05 % for NdIII . The ability to control 1 O2 generation through the excitation wavelength indicates that the incorporation of 2,2':5',2''-terthiophene results in access to multiple sensitization pathways. These energy pathways are unraveled through transient absorption spectroscopy.

Luminescent Carbazole-Based EuIII and YbIII Complexes with a High Two-Photon Absorption Cross-Section Enable Viscosity Sensing in the Visible and Near IR with One- and Two-Photon Excitation.

The newly synthesized EuIII and YbIII complexes with the new carbazole-based ligands CPAD2- and CPAP4- display the characteristic long-lived metal-centered emission upon one- and two-photon excitation. The EuIII complexes show the expected narrow emission bands in the red region, with emission lifetimes between 0.382 and 1.464 ms and quantum yields between 2.7% and 35.8%, while the YbIII complexes show the expected emission in the NIR region, with emission lifetimes between 0.52 and 37.86 µs and quantum yields between 0.028% and 1.12%. Two-photon absorption cross sections (σ2PA) as high as 857 GM were measured for the two ligands. The complexes showed a strong dependence of the one- and two-photon sensitized emission intensity on solvent viscosity in the range of 0.5-200 cP in the visible and NIR region.

Secondary-Sphere Chlorolanthanide(III) Complexes with a 1,3,5-Triazine-Based Ligand Supported by Anion-π, π-π, and Hydrogen-Bonding Interactions.

2,4,6-Dipicolylamine-functionalized 1,3,5-triazine (dpat) was isolated. When reacted with LaCl3, compound [(LaCl6)(H3dpat)][H2O]2 (1) formed, which crystallized in the monoclinic P21/n space group with parameters a = 11.47 Å, b = 19.22 Å, c = 20.98 Å, V = 4652.02 Å, and ß = 90.53°. When reacted with NdCl3, the complex [NdCl3(H2O)4(H3dpat)][Cl]3(MeOH)2 (2) crystallized in the monoclinic P21/n space group with unit cell parameters a = 20.05 Å, b = 12.81 Å, c = 20.64 Å, V = 5004.40 Å, and ß = 110.20°. In both cases, the dpat ligand forms a bowl-shaped cavity that partially envelops the LnIII-containing central unit, which is anionic in 1 and neutral in 2. The formation of these outer-sphere complexes is supported by secondary interactions, including π-π stacking, hydrogen bonding, and anion-π between the chlorolanthanide(III) fragment and the electron-deficient 1,3,5-triazine ring. Evidence of protonation of the pyridine rings in dpat was substantiated through the isolation of [H2dpat][Cl]2 (3). This compound crystallized in the monoclinic C2/c space group with parameters a = 11.93 Å, b = 20.22 Å, c = 15.28 Å, V = 3664.97 Å, and ß = 94.35°. Four pyridine rings are pairwise protonated in 3. dpat showed a moderate ability to extract LaIII from an aqueous to an organic phase, indicating its potential, through judicious manipulation of secondary-sphere interactions, as the starting point for efficient extractants for LnIII ions.

1O2 Generating Luminescent Lanthanide Complexes with 1,8-Naphthalimide-Based Sensitizers.

Lanthanide ion (LnIII) complexes with two new 1,8-naphthalimide-based ligands, Nap-dpe and Nap-cbx, were isolated, and their photophysical properties were explored. Upon excitation at 335 nm, Nap-dpe and Nap-cbx sensitize visible and near-infrared emitting LnIII ions (LnIII = EuIII, NdIII, and YbIII) and generate singlet oxygen (1O2). The quantum yields of EuIII luminescence for [Eu(Nap-cbx)3]3+ and [Eu(Nap-dpe)3]3+ are 16.7% and 8.3%, respectively, with 1O2 generation efficiencies of 41% and 59%, respectively. The efficiencies of 1O2 generation for the NIR emitting complexes [Ln(Nap-dpe)3]3+ are 59% and 56%, respectively, and those for [Ln(Nap-cbx)3]3+ (LnIII = NdIII, YbIII) are 64% and 61%, respectively. In an oxygen-free environment, the quantum yields of EuIII luminescence for [Eu(Nap-cbx)3]3+ and [Eu(Nap-dpe)3]3+ increase to 20% and 18%, respectively.

Anion-π and H-Bonding Interactions Supporting Encapsulation of [Ln(NO3)6/5]3-/2- (Ln = Nd, Er) with a Triazine-Based Ligand.

Reaction of NdIII and ErIII nitrate salts with a 1,3,5-tris(dipicolylamine)-triazine (dpat) ligand yielded two unprecedented examples of [Ln(NO3)6/5]3-/2- (Ln = Nd, Er) moieties completely encapsulated by the ligands. They are found in the two new complexes, [(H3dpat)2][(Nd(NO3)6)2]·2CH3CN (1), and the related [(H3dpat)2][(Er(NO3)5)3]·3CH3CN·2H2O (2). The structures of the complexes are similar and they crystallize in the triclinic P-1 space group with a = 12.1630(3), b = 12.2694(3), c = 17.6357(5) Å, V = 2611.10(12) Å3, and a = 14.3372(4), b = 17.1271(4), c = 25.2207(7) Å, V = 5934.7(3) Å3, respectively. Anion-π interactions, which are reported here for the first time for LnIII ion complexes, hydrogen bonding interactions and π-π stacking support the formation of the encapsulated species. Evidence of the protonated dpat ligand in 1 and 2 was found through isolation of (H2dpat)(NO3)2. Finally, the pH-dependent ability of the ligand to extract LaIII and nitrate ions from aqueous into toluene solution is demonstrated.

Synthesis, Structure, Photophysical Properties, and Photostability of Benzodipyrenes.

This work explores the syntheses, structures, photophysical properties, and photostability of benzodipyrenes (BDPs). BDPs were synthesized through an InCl3 -AgNTf2 -catalyzed, four-fold alkyne benzannulation reaction. The structures of BDP 4 a and its corresponding endoperoxide product were unambiguously confirmed by X-ray crystallography. The BDPs reported here can also be recognized as peri- and cata-benzannulated pentacenes with a non-functionalized central ring. Unlike the previous reported pentacene-based polycyclic aromatic hydrocarbons, the absorbances of the BDPs were blueshifted by ca. 40 nm relative to pentacene, even after extension of π-conjugation. The newly synthesized BDP products exhibit relatively good stability with half-lives as high as 4612 min in THF.