Photophysics of Coumarin and Carbostyril ... - ACS Publications

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Photophysics of Coumarin and Carbostyril-Sensitized Luminescent Lanthanide Complexes: Implications for Complex Design in Multiplex Detection Daniel Kovacs,† Xi Lu,‡ Lívia S. Mészáros,† Marjam Ott,‡ Julien Andres,*,† and K. Eszter Borbas*,† †

Department of Chemistry, Ångström Laboratory, Box 523, Uppsala University, Uppsala 75120, Sweden Department of Engineering Sciences, Ångström Laboratory, Box 534, Uppsala University, Uppsala 75121, Sweden

‡

S Supporting Information *

ABSTRACT: Luminescent lanthanide (Ln(III)) complexes with coumarin or carbostyril antennae were synthesized and their photophysical properties evaluated using steady-state and time-resolved UV−vis spectroscopy. Ligands bearing distant hydroxycoumarin-derived antennae attached through triazole linkers were modest sensitizers for Eu(III) and Tb(III), whereas ligands with 7-amidocarbostyrils directly linked to the coordination site could reach good quantum yields for multiple Ln(III), including the visible emitters Sm(III) and Dy(III), and the near-infrared emitters Nd(III) and Yb(III). The highest lanthanide-centered luminescence quantum yields were 35% (Tb), 7.9% (Eu), 0.67% (Dy), and 0.18% (Sm). Antennae providing similar luminescence intensities with 2−4 Ln-emitters were identified. Photoredox quenching of the carbostyril antenna excited states was observed for all Eu(III)-complexes and should be sensitizing in the case of Yb(III); the scope of the process extends to Ln(III) for which it has not been seen previously, specifically Dy(III) and Sm(III). The proposed process is supported by photophysical and electrochemical data. A FRET-type mechanism was identified in architectures with both distant and close antennae for all of the Lns. This mechanism seems to be the only sensitizing one at long distance and probably contributes to the sensitization at shorter distances along with the triplet pathway. The complexes were nontoxic to either bacterial or mammalian cells. Complexes of an ester-functionalized ligand were taken up by bacteria in a concentration-dependent manner. Our results suggest that the effects of FRET and photoredox quenching should be taken into consideration when designing luminescent Ln complexes. These results also establish these Ln(III)-complexes for multiplex detection beyond the available two-color systems.

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INTRODUCTION

spectra result in spectral overlap, greatly reducing their utility, in particular when the fluorophores are colocalized. To prevent spectral cross-talk, fluorophores with large Stokes shifts and narrow emission bands are desirable. Lanthanide coordination complexes bearing sensitizing chromophores have proved over the past decade to be exceptional tools for multiplex imaging.20 This is because they emit sharp long-lived emission bands across the whole visible-NIR spectrum depending on the trivalent Ln-ion while retaining the same absorption range, which only depends on the sensitizer. In addition to their large apparent Stokes shifts, luminescent Lns have spectral fingerprints with transitions always at the same energy, and emission decays in the microsecond to millisecond range. This enables time-resolved detection to remove background fluorescence, as well as lifetime-based multiplexing, a strategy exploiting the large differences in Ln excited-state lifetimes.21

Complexity is a defining character of living organisms, and is certainly the major challenge to understanding even the most basic forms of life. Investigating the diversity of cellular structures, processes, and their spatiotemporal dynamics requires minimally invasive multiplex imaging tools to simultaneously probe several parameters without disrupting the observed objects. Multiplex imaging provides unprecedented accuracy in diagnostics,1,2 contributes to personalized medicine,3 and is indispensable for the deciphering of cellular communication networks4,5 and biomolecule interactions.6,7 Fluorescent tags and probes emitting in the visible to nearinfrared (NIR) part of the spectrum are continuously improved in terms of photostability, brightness, cell permeability, sensitivity, and targeting ability.8−13 Small molecule fluorophores are particularly interesting as their properties are readily tuned, and they can be derivatized to incorporate specific functions.14−19 The challenge of using organic fluorophores in a multiplex context is that their broad absorption and emission © 2017 American Chemical Society

Received: October 29, 2016 Published: April 7, 2017 5756

DOI: 10.1021/jacs.6b11274 J. Am. Chem. Soc. 2017, 139, 5756−5767

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Journal of the American Chemical Society

Chart 1. Structures of the Triazole-Linked do3a (1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic Acid, Lc)- and dota (1,4,7,10Tetraazacyclododecane-1,4,7,10-tetraacetic Acid, Ld)-Based Ligands of the Complexes Studied Here

composed of six different Lns coordinated to the same ligand is reviewed for the simultaneous multiplex detection of six or seven colors (i.e., six Ln channels and one additional fluorescent channel), which has, to our knowledge, never been attempted before. Coumarins and carbostyrils are well-known antennae,45−59 and as mentioned, multiplex imaging in cells is an established technique that has already been successfully used with Ln complexes. This study has two major findings. (1) The first is the unprecedented demonstration that a mixture of analogous complexes can afford six-color multiplex detection, with a potentially seventh-color channel available using the antennae fluorescence. (2) The extensive set of ligands and complexes enabled us to decipher the sensitization pathways and rationalize the contribution of often neglected mechanisms (photoinduced electron transfer (PeT), fluorescence resonance energy transfer (FRET), and back energy transfer (BET) onto the triplet state). PeT is of particular interest: until now, only Eu and Yb were observed to undergo PeT. Here, we present experimental and thermodynamic evidence that PeT may occur with Sm, Dy, and Nd. FRET, that is, a singlet excited-state energy transfer onto the Ln ion, which is known to operate in certain complexes,60,61 was also investigated. Our data prove that the singlet excited state is an important component of Lnsensitizers that deserves more attention and provides alternative photophysics.

The simplest way to perform multiplex imaging with Lncomplexes is to combine the same ligand with different Ln-ions and rely on the Ln-photophysics to address multiple detection channels. The chemical similarity of the Lns means that complexes with identical coordination geometries (i.e., containing Lns of similar size) have similar cellular uptake mechanisms and intracellular localizations.22,23 Multiplex imaging with Ln-complexes thus requires antennae that can sensitize several Lns. Leading examples are pyridine-based Pybox24,25 and bis-tetrazole-pyridine antennae,26 sensitizing 9 and 10 emitters, respectively. A Ga(III)/Ln(III)-metallacrown27 and phenanthroline28 could each sensitize 9 ions. Several systems with 4−5 emissive Ln’s have also been reported.29−33 Nevertheless, these emitters are not amenable to responsive imaging; that is, they do not alter their luminescence properties (e.g., emission intensity, lifetime, or excitation wavelength) upon external stimuli; methods to turn them into responsive probes are currently unavailable. Furthermore, they often have short excitation wavelengths, low aqueous stabilities, and lack straightforward derivatization chemistries for bioconjugation. A single antenna usually affords bright emission with only 1− 2 Ln-emitters, the rest of the Ln-centers staying weakly emissive. Improving the performance of these complexes requires understanding of the sensitization mechanism, which is an intricate process dependent on the antenna, the complex structure, the chemical environment, the temperature, and the Ln-ion.34−39 Excitation of the visible-emitting Lns is usually limited to UV-blue light. However, two-photon excitation with red/NIR light is increasingly widespread and avoids damage to biomolecules.40−44 Here, we report a structure−photophysics study of 61 Ln complexes based on 14 ligands carrying either coumarin or carbostyril sensitizers. The most efficient sensitizers are brightly luminescent and photostable. Promising antennae, identified with the Gd, Eu, and Tb complexes, are also studied with Dy, Sm, and NIR-emitting Yb and Nd. We have identified several antennae able to sensitize four visible-emitting Lns, as well as NIR-emitting Yb and Nd. To assess their viability in biological applications such as for multiplex fluorescence imaging in vivo, the complexes are tested both in a mammalian cell line and in bacteria. Finally, the potential of a cocktail of six Ln complexes

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RESULTS AND DISCUSSION Ligand Design. Coumarins and carbostyrils are among the synthetically most malleable antennae for Tb and Eu.45,47,62 Nevertheless, systematic structure−activity studies are lacking, and in-depth photophysical investigations are rare.49,60,63 Both chromophores are amenable to responsive probe development using a variety of strategies.48,54−56,64 Their Eu(III) and Tb(III)-chelates are excellent LRET donors45 for monitoring protein−protein interactions,65 and have been used to follow the voltage-dependent conformational changes in ion channels.66 A carbostyril-modified (3Me, Chart 1) unnatural amino acid was incorporated into a Ln-binding peptide sequence, which could be grafted onto larger proteins. Loading with Tb(III) or Eu(III) yielded green or red luminescent-proteins 5757


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Scheme 1. (a) Alternative Syntheses (Routes A, B) of LnLc from Hydroxycoumarins 1x;a and (b) Synthesis of Ld-Complexes

a

Bim(Py)2: N-((1H-benzo[d]imidazole-2-yl)methyl)-1-pyridin-2-yl)-N-(pyridine-2-ylmethyl)methanamine.

upon 337 nm-excitation.67 However, applications have been limited to Eu(III) or Tb(III), and the most widely used 3Me antenna is an ineffective sensitizer for Eu(III).46 Two sets of ligands were designed (Chart 1). They are based on the cyclen framework, which has been used extensively in both luminescent and MRI-active Ln-bioprobes.68−71 The first is derivatized by a coumarin linked to a do3a (1,4,7,10tetraazacyclododecane-1,4,7-triacetic acid) moiety through a triazole. Such systems have improved Ln-photophysical properties as compared to those with longer linkers.56 The second set is based on dota (1,4,7,10-tetraazacyclododecane-1,4,7,10tetraacetic acid) linked through one of the carboxylic acids to a 7-amino carbostyril or 7-amino coumarin. Similar complexes with a short antenna−Ln distance and an octadentate coordination site are known for a few 7-amino-carbostyrils.45,47 Synthesis. LnLc-complexes were prepared analogously to a previously reported procedure (route A, Schemes 1 and S1).57 The bottleneck of the synthesis was the alkylation of the secondary amine of a do3a-core with a tosylated coumarin derivative. This afforded low yields of the product that was difficult to purify. We have reported an efficient Cu-catalyzed cycloaddition of azido-Ln-complexes and alkynes (route B, Scheme 1).56,72 The reaction of Ln7 with 6Me afforded the products in 43% (Ln = Eu) and 54% (Ln = Lu) yield after column chromatography. The chemical and photophysical properties of the complexes obtained by the two routes were identical. The late-stage functionalization is a good alternative to stepwise synthesis, especially for the introduction of sensitive functional groups. Ligands H3Ld-3x, H3Ld-4, and H3Ld-5 were prepared via a series of N-alkylations from cyclen (9) and the appropriate Nchloroacetylated coumarins or carbostyrils (Schemes 1 and S2− S4). Conditions were optimized to overcome the low solubilities of some of the intermediates leading to H3Ld-3x and the propensity of the carbostyril amides for N-alkylation. The precursors of H3Ld-4 and H3Ld-5 displayed good organic solubilities, were readily purified and characterized, and did not

undergo significant side-reactions. The free triacid ligands H3Ld-x were isolated in pure form after column chromatography. Recently, the importance of the complexation procedure was highlighted by showing that kinetic and thermodynamic complexes with different photophysical properties can be differently distributed in solution and in the isolated product.73 The long and flexible triazole-based linker in the Lc-ligands required forcing conditions for complete complexation. Excess Ln-ions could be removed using a chelex-100 chelating resin previously used for the purification of Gd-chelate MRI contrast agents.74 However, most of the complex was also retained in the resin even after extensive washing. As we did not observe any significant photophysical difference between solutions devoid of free Ln-ions and solutions with free Ln-contents, we performed spectroscopic characterization of the untreated complexes (Figures S1 and S2). Nevertheless, for applications requiring samples free of Ln-ion traces, this purification step is possible. Without desalting, the samples were estimated to contain 25−50% of complex; excess salt alone can account for most of the additional mass. The synthetic intermediates, the ligands, and the diamagnetic Lu-complexes were characterized by 1H and 13C NMR spectroscopy and high-resolution mass spectrometry. The analytical data were in line with the expected structures. The purities of the complexes were assessed by RPHPLC analysis. Finally, the photophysical characterization of all Ln complexes was performed, which is discussed below. For a detailed discussion of the syntheses, see the Supporting Information. Photophysical Studies. LnLc and LnLd were both studied in water, LnLc in buffered HEPES (0.1 M at pH 7.0), and LnLd in unbuffered water (measured pH range 6.0−7.0, Table S2) similarly to previously reported complexes.46,49,57 Concentrations were set at 10 μM for LnLc and around 30 μM for LnLd (see Table S8 for the exact values). The influence of pH on the properties of the emitter is important for biological applications.36,75−79 The emission 5758


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Journal of the American Chemical Society spectra of TbLd-34Me and TbLd-34CF3 were recorded between pH 1−10 (Figures S3−S6). The luminescence of both the antennae and the Ln-ions is quite stable in acidic solutions. Above pH 7.4, both luminescent signals decrease, and at pH 10−11, more than 90% of the Ln-intensity is lost. By using a simple single proton equilibrium model and fitting the Ln signals, pKa values of 7.7 and 9.5 are found for TbLd-34CF3 and TbLd-34Me, respectively. As expected, electron-withdrawing groups on the antenna make this proton more acidic. The signal loss is due to antenna deprotonation and not to a modification of the coordination sphere, as shown by the invariance of the Eu-emission fingerprint.80 A titration was performed with EuLd-44CF3, which has no core NH, and a similar emission intensity decrease was noted, with an intermediate pKa of 8.4. These data point to a 7-amido NH deprotonation that alters the properties of the antennae and diminishes the Ln-sensitization efficiency. These results are similar to those found for similar amide-carrying quinolonesensitized Eu-complexes.81 Ligand-Centered Photophysics. The coumarin and carbostyril antennae in the Lc and Ld series have a range of electronwithdrawing and -donating auxochromes, different degrees of steric hindrance, as well as reactive handles for further derivatization (Chart 1). Lc, Ld-4, and Ld-5 ligands contain coumarins, and the Ld-3x ligands contain carbostyrils. Characteristic absorption and emission spectra of LnLc and LnLd-complexes are shown in Figures 1, 2, and S7−S11. The

Figure 2. Excitation (left, black, 298 K), steady-state fluorescence (middle, red, 298 K), and phosphorescence (right, blue, 77 K) emission spectra of selected GdLd-complexes. (A) -33Es, (B) -3MOM, (C) -5. Excitation at λex = 345 nm for (A) and (B) and at λex = 320 nm for (C). Concentration 30 μM, in H2O, pH between 6.0 and 7.0 (see Tables S1 and S8). See the Supporting Information for corrected concentrations.

position (e.g., Lc-1CF3, Ld-3CF3, and Ld-4CF3); electrondonating groups induce a hypsochromic shift of the absorption and emission (e.g., Lc-27OMe). The triplet states are similarly affected: Ld-4CF3 is particularly red-shifted (more than the carbostyril analogue) and has the lowest lying triplet state in our study (20 800 cm−1), while Lc-27OMe has the highest lying triplet state (25 000 cm−1). The LnLc extinction coefficients are reasonably high (17 000−25 000 M−1 cm−1; see Table 1). LnLd has somewhat lower ε(max) values, 11 000−16 000 M−1 cm−1 for Ld-3 and 5059 cm−1 for Ld-5. The extinction coefficients of LnLd are comparable to values reported previously for ligands containing 3Me and 3CF3.82 The antenna fluorescence quantum yields (ΦL) of 7alkoxycoumarins in LnLc were modest to high, between 6% and 49% (Tables 2 and 3). The ΦL values of the 7aminocarbostyrils in Ld-3x are modest (2%, except for TbLd4CF3. The highest quantum yield of this study for an Eu complex is found for EuLd-3CF3 (8%), and all of the other EuLd complexes are between 1−4%. From a state-of-the-art perspective, top emitting TbLd-3x complexes range among the most emissive Tb-species.91−94 This is quite remarkable as such emitters are nearly exclusively complexes devoid of water molecules in their first coordination spheres. Dy- and Sm-emissions were already measured on LnLc-1Me and gave promising results with a ΦLn of the DyLc-1Me at 0.1%.57 There is a dearth of efficient Dy and Sm sensitizers. Therefore, we decided to extend our study to include the Dyand Sm-complexes of the Ld ligands, all of which give observable Dy- and Sm-emissions. In DyLd-34MOM and DyLd-5, the Dy-emissions even have peak intensities comparable to the maximum intensity of the residual fluorescence, which is rare enough to be highlighted. The maximum ΦLn values were measured in Ld-3Me and Ld-3MOM for Dy (0.67%) and Sm (0.16%), and in Ld-3CF3 for Sm (0.18%). Comparisons with reported values are difficult as values are often recorded in the solid state or aprotic solvents and not water. However, a dinuclear helicate with ΦSm = 0.38%95,96 and a Sm-containing dendrimer with ΦSm as low as 0.022% (in DMSO)97 were successfully used in microscopy; even biphotonic microscopy was possible with a somewhat more emissive mononuclear species (ΦSm = 0.91%).98 This suggests that the most emissive SmLd-3x complexes are promising luminophores for bioimaging. Dy is even less used than Sm. DyLd-3Me, DyLd-3MOM, and DyLd-33Es are brighter than some of the Eu-emitters utilized in live cell imaging, and provide emission bands in regions distinct from Eu, Tb, and Sm (vide infra). Encouraged by these promising results, we prepared Yb- and Nd-species YbLd-3Me, YbLd-33Es, and NdLd-33Es. All of these complexes displayed Ln-centered emission in the NIR upon antenna excitation (Figure 5). In the case of Ld-33Es, this translates into the sensitization of 6 Ln-ions with the same antenna. We have not been able to measure their ΦLn and τLn with our setup. However, as autofluorescence is negligible in the NIR, microscopy with even weakly luminescent Yb-emitters is feasible.99,100 Upon time resolution, the antenna fluorescence is removed, and only the Ln-transitions are observed. Some of the Dy- and Sm-complexes that were emissive under steady-state conditions were not resolvable with our time-gated setup, which has a flash lamp with a 5−10 μs pulse tail and a 0.04 ms limit on the timegate. The lifetimes of the Dy- and Sm-complexes are thus too short to be separated from the fluorescent emission, and therefore their τLn given in Table 3 should be taken with caution. Interestingly, the time-resolved emission spectra were often contaminated with, or completely dominated by, Tbsignals, while Eu-assigned peaks were observed in Yb- and Sm-

Figure 5. Excitation [left, black, λem = 875 nm (Nd), λem = 980 nm (Yb)] and steady-state emission (in color, λex = 344 nm) spectra of NdLd-33Es and YbLd-33Es.

spectra (see, e.g., Figures S29 and S31). The Tb and Eu were shown to come from reagent by control experiments. By ICPMS-analysis, the levels of Tb and Eu were 0.99 and 0.13 ppm in SmCl3 and YbCl3, respectively. Thus, low picomolar concentrations of Eu3+ and Tb3+ can be detected with luminescence spectroscopy against an emissive background, without optimization of the detection conditions. This suggests that timeresolved emission could be a cheap method for monitoring subppm-levels of Tb and Eu in Ln-salts, which is important during the production of phosphor grade (99.999%) materials for electronics and spectroscopy. Overall, the Lc-ligands Lc-3Es and Lc-3cHex have the top efficiencies for both Eu and Tb. In the Ld series, 3Me, 3MOM, and 33Es are the best candidates because of their excellent Tbluminescence and good Eu-brightness, with ΦEu around 3%. The Ld-33Es and Ld-3MOM antennae are particularly attractive because they enable further chemical modifications. Ld-3MOM complexes are even more efficient Dy- and Sm-sensitizers than Ld-33Es. The sensitization process is easily quantified by the sensitization efficiency (ηsens) and an intrinsic quantum yield (Φintr,Ln) that define the overall quantum yield (ΦLn), as expressed in eq 1 (kr,Ln = 1/τr,Ln is the radiative rate constant of the Ln, knr,Ln is the nonradiative relaxation rate constant of the Ln, and τLn = 1/Σi ki,Ln is the observed lifetime of the Ln). ΦLn = ηsens ·Φintr,Ln = ηsens ·

k r,Ln k r,Ln + ∑nr k nr,Ln

= ηsens ·

τLn τr,Ln (1)

Ln-spectra are mostly unaffected by the environment. The energies of the different spectroscopic levels are always at the same values, even though the coordination sphere and its ligand field define the splitting and oscillator strengths of each transition.101 In this regard, Eu has a unique magnetic dipole transition (5D0 → 7F1) with an intensity that is independent of the environment and can therefore serve as an internal standard for calibrating the other transitions. The radiative rate constant (kr,Ln) of the Eu (5D0) level can be estimated as a result of this feature.80 The same Ln-ions bound to ligands in the same series have similar spectra, showing that within a given architecture antenna variation does not affect the Ln-coordination. On the other hand, a comparison of the Lc and Ld architectures reveals differences in their Eu spectra. In EuLd, the major transition is the 5D0 → 7F4 manifold, whereas in EuLc, both the 5D0 → 7F2 5762


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Journal of the American Chemical Society and the 5D0 → 7F4 transitions have similar intensities (see Figures 3 and 4), characteristic of dota Eu-complexes.45,46 The alteration of the spectral fingerprint reflects a change in the coordination sphere of the Ln-ion and is in agreement with the octadentate coordination environment. The hydration numbers (q) were calculated to be 1.5 in EuLc and 1.0 in EuLd from the Ln-lifetime differences in H2O and D2O.35,102 This suggests a weaker coordination of the soft triazole donor that is forced into a less favored six-membered ring, than the hard amide donor. The hydration numbers are similar to previously found values.103 Antenna-dependent quenching processes made the model inapplicable for Tbcomplexes. There is no significant variation of the Eu τLn within the same architecture. EuLc lifetimes are around 0.44(3) ms, and those of EuLd are around 0.60(2) ms. The radiative lifetimes of the 5 D0 spectroscopic level, calculated from the integration ratio of the magnetic dipole transition relative to the integration of the whole Eu-spectrum,80,104 are estimated at 4.2 ms in the Lc ligands and 5.4 ms in the Ld environment. As shown in eq 1, the ratio of the observed lifetime over the radiative lifetime gives the intrinsic quantum yield of the Ln-ion. Unexpectedly, EuLd do not have significantly higher intrinsic quantum yields than EuLc (10% vs 11%, respectively), even though the higher hydration of do3a-based complexes would be expected to have more quenching by OH vibrations and therefore lower intrinsic quantum yields. The increased intensity of the 5D0 → 7F4 transition in the EuLd complexes is responsible for the much higher Eu radiative lifetime in LnLd, canceling the benefits of the lower q. Despite the fact that radiative lifetimes and intrinsic quantum yields of Tb complexes are not easily accessible, observed lifetimes (τLn) and overall quantum yields (ΦLn) can give a good idea of the efficiency of the Tb luminescence in a given system. As for Eu, the radiative lifetime should not be dramatically affected by the variation of the antenna. Therefore, τLn is a good indicator of Ln quenching. By plotting the decay rate constant kLn = 1/τLn as a function of the energy of the triplet state, we observe a clear quenching trend that decreases as the energy increases above the Tb 5D4 spectroscopic level (Figures S44 and S45). This is the case both in the Lc series and with Ld-3x ligands (Ld-44CF3 was omitted because its Tb emission is too low to give reliable data). The same phenomenon is highlighted by plotting ΦLn instead of the rate constant. A similar correlation between the energy of the sensitizer’s triplet state and its ΦLn was already observed by Latva and co-workers and attributed to energy back transfer onto the triplet state due to the small energy gap between the Tb 5D4 spectroscopic level and the triplet state.91 Energy back transfer to coumarin chromophores in similar architectures, including Lc, was supported by deoxygenation experiments.55,56 Concerning the Eu complexes, no clear relationship between the triplet state location and the luminescence of Eu in either series could be extracted (Figure S46). However, the sensitization efficiency seems to increase steadily when the energy of the singlet excited state of the Ld complexes is reduced. This could be due to a correlation between the singlet excited-state energy and the energy gap between the singlet excited state and the triplet. In EuLc, ΦLn is linearly correlated with ΦL (Figure S47). Antennae with singlet excited states that are already deactivated in the corresponding Gd-complexes are thus not good candidates. It also suggests that the sensitization could happen

via the singlet excited state, the energy transfer rate for Förster energy transfer being inversely proportional to the radiative lifetime of the donor, that is, radiative fluorescence lifetime of the antenna. This has already been reported for distant coumarins.60 Furthermore, it implies that accurate evaluation of potential factors influencing the sensitization of Ln-ions in this series should be evaluated on ΦL normalized ΦLn to take into account the scaling by fluorescence. In LnLd, this fluorescence scaling effect is not observed, but it could be due to low ΦL values that are not important enough to meaningfully impact ΦLn. Attribution of a sensitization mechanism without detailed time-resolved measurements on different time scales is unreliable, because of the intricate photophysical processes between Ln-ions and antennae. For example, quenching of the antenna phosphorescence is often observed at low temperature (77 K), and is often taken as a sign of triplet sensitization. Nevertheless, other mechanisms could produce apparent phosphorescence quenching. It has already been demonstrated by triplet−triplet transient absorption that quenched phosphorescence at 77 K observed under steady-state conditions does not always yield the expected quenching of the triplet state lifetime at room temperature.60 Furthermore, the phosphorescence at 77 K can be very long-lived (up to seconds), which makes it difficult to observe, and nevertheless precludes any sensitization happening on a shorter time scale. Lc-14Me has been reported to have phosphorescence decay with a 1.5 s lifetime.57 Two explanations can rationalize this long lifetime and the quenching of the steady-state phosphorescence at 77 K. (1) The triplet state is not involved in the sensitization, but a level feeding the triplet state is, which decreases the overall population of the triplet. (2) Alternatively, the phosphorescence comes from a fraction of the complexes in which the transfer is ineffective, which implies that there is a very fast component in the decay coming from complexes where the energy transfer occurs, but this component is not measurable on the probed time scales or the fraction is too small as compared to the bulk. The behavior of TbLd seems to agree with a triplet state sensitization, but it could also be a purely quenching state while sensitization takes place from a higher excited state (singlet or spectroscopically silent level). It is unlikely that the sensitizing state is the fluorescent state of Ld ligands. The quenching of ΦL is indeed not large enough to explain the exceptional ΦLn of TbLd-34Me for example. Nevertheless, a small part of the sensitization could come from the singlet excited state. Although EuLd apparently has sensitization efficiencies that depend more on the singlet excited-state energy than that of the triplet, it is the singlet−triplet energy difference that seems to impart an exponential growth on the sensitization efficiency with decreasing energy gap. In case of a triplet sensitization pathway, this could be explained by the increased intersystem crossing rate as the energy gap diminishes, as expected by Siebrand’s energy gap law.105 Lc complexes only show an energy gap law behavior on their ΦL, which increases with increasing energy gap and hence decreasing intersystem crossing and internal conversion. Because ΦLn and thus ηsens follow ΦL in EuLc, their ηsens values are not correlated to the intersystem crossing rate (Figures S44−S57). Singlet energy transfer onto the Ln results in a quenching of the fluorescence. We pointed out previously that PeT could be responsible for the different quenching observed upon variation of the Ln-ion with the same antenna. However, the PeT 5763


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Journal of the American Chemical Society mechanism seems not exclusive and can actually not explain the growth of the quenching along the following series: Tb < Yb < Nd < Dy < Sm < Eu. If PeT were solely responsible for the quenching of the ligand singlet excited states, Yb should be between Sm and Eu because its reduction potential lies between those two Lns. Yb has a single excited spectroscopic level, whereas the other Lns have levels higher than their lowest luminescent level. This means that direct transfer from the singlet excited state to the Yb 2F5/2 spectroscopic level should not occur because there is no spectral overlap between the donor and acceptor levels. Thus, quenching of its ligand excited state should be entirely due to PeT. Because Yb luminescence is observed, PeT between the ligand and Yb is eventually sensitizing Yb, as proposed by Horrocks and co-workers.106 If we consider that the quenching in the other complexes is a combination of PeT and S1 energy transfer onto the Ln ion (i.e., FRET), at the opposite side of the combinatorial scheme, Tb has a reduction potential that is high enough to preclude any PeT from happening. The quenching of S1 by Tb is therefore purely by energy transfer onto Tb. Assuming that all of our tested Lns except for Yb have similar S1 energy transfer efficiencies, the observed order of quenching follows the reduction potentials of the Ln ions (see Figure S58). In summary, both PeT and energy transfer onto Ln from the singlet excited states are feasible quenching mechanisms for the ligand singlet excited states. In the case of Tb and Yb, only energy transfer or PeT can occur, respectively. Intersystem crossing is also another quenching mechanism, but should not be drastically different for a given ligand when only the Ln is changed. The Lc complexes seem to conform to a Förster-type energy transfer, because the sensitization efficiency depends on ΦL, and hence on the donor radiative lifetime. This is expected as the distance between the antenna and the Ln ion is too large for a Dexter mechanism. On the other hand, the Ld complexes have the antenna close to the Ln ion and could be sensitized by a different and more efficient mechanism. Sensitization by the Ld antenna triplet states appears in this case reasonable, but would require detailed time-resolved measurements to exclude other possibilities. Cellular Imaging. The emissive LnLd-complexes were evaluated for their potential in cellular imaging (Figure 6, and S59−S68). The photostabilties of LnLd-33Es (Ln = Eu, Tb, Yb) were compared to a NIR cyanine dye (Figure S59). After 90 min of irradiation, EuLd-33Es and YbLd-33Es retained >80% of their emission. For TbLd-33Es, this value was >70%. Under the same conditions, the organic fluorophore essentially completely decomposed. This experiment confirms the high photostability of Ln-complexes, as even the most sensitive Tb-species were significantly more robust than the cyanine dye. Direct incubation of MC3T3-E1 cells (a preosteoblastic cell line) with LnLd for up to 72 h shows no or only a slight reduction in cell viability (>80% viable relative to negative control, Alamar blue assay) for the majority of the compounds at the tested concentration after 24 h. Three compounds showed approximately 30% reduction in cell viability as compared to the negative control. Of these three groups, two showed some recovery and cell viability that is greater than 80% as compared to controls at 72 h (Figure S60). In E. coli, TbLd33Es did not affect bacterial life ability even at the highest tested concentration, [TbLd-33Es] = 500 μM. LnLd-33Es were taken up by bacteria in a concentration-dependent manner (Figures

Figure 6. (a) Intracellular detection of a mixture of TbLd-33Es and EuLd-33Es (Eu:Tb = 8.5:1.5, [LnLd-33Es = 250 μM]) in live E. coli (100 mM Tris HCl, pH 7.0, λex = 344 nm, flash count = 4, front slit = 10 nm, exit slit = 10 nm, initial delay = 0.07 ms, sample window = 0.2 ms). (b) Time-resolved fluorescence spectra of a four-component solution, recorded with different sample windows (0.01 ms, top, and 1 ms, bottom), DyLd-33Es, SmLd-33Es, and EuLd-33Es ([LnLd-33Es] = 15 μM for Ln = Dy, Sm, [EuLd-33Es] = 46 nM, traces [TbLd-33Es] = 2.7 nM). Flash delay = 0.04 ms, λex = 344 nm. Blue rectangles, Dysignals; green rectangles, Tb-signals; red rectangles, Eu-signals; orange rectangles, Sm-signals; gradient shade, overlapping signals arising from several lanthanides. (c) The NIR-range of the mixture in (b), containing varying concentrations of YbLd-33Es and NdLd-33Es. Spectra were adjusted at 795 nm to remove inner-filter effects. 5764


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sensitization pathways contributing to Ln-emission in most of the metals. The quantum yields of the complexes bearing close antennae are better than distant ones, and 20−60% as efficient as the commercially available Lumi4 complexes33 used as RET donors to organic acceptors in multiplex imaging.1 Crucially, time-resolved techniques and NIR detection both result in diminished sample backgrounds, which means that even low quantum yield systems (such as LnLc) are amenable to biological applications.55,56,99 Further improvement to the performance of these Ln-emitters may be achieved by completely excluding water molecules from the Ln-coordination sphere by modifying the ligand structure to introduce a ninth donor atom. Up to six Lns could be sensitized by the same antenna that could also be easily chemically derivatized to fit desired applications. These six luminescent Ln channels have little overlap, and, when the antenna fluorescence is used, can yield seven distinct bands across the visible and the NIR, making these complexes very interesting for multiplex imaging; the coupling of two of these complexes together should also enable ratiometric detection.20,110,111 The Ln-complexes exhibited excellent resistance toward photobleaching, which is beneficial for experiments requiring long exposure times. The LnLd-33Es complexes were taken up by bacteria, without obvious signs of detrimental effects on cell growth and proliferation; the complexes were amenable to one- and two-color intracellular detection in living bacteria. Greater than 80% cellular viability was observed in a mammalian cell line for the majority of the complexes. In solution, a seven-color simultaneous detection was demonstrated including four visible Lns, two NIR Lns, and the antenna fluorescence.

S69 and S70), and incubation concentrations as low as [TbLd33Es] = 5 μM could be applied. TbLd-33Es and EuLd-33Es could be detected inside living bacteria separately as well as a cocktail of two Ln-complexes (Figures 6a, S61, and S62) by either a steady-state or a time-resolved method. Nevertheless, timeresolved spectra greatly enhanced the Ln-signals and facilitated the identification of the different Ln-fingerprints. The complexes were mostly located in the cytoplasm, as shown by cell fractionation (Figures S63−S68). We have not yet investigated the uptake mechanism of the Ln(III) complexes; we note that in mammalian cells the mechanism is strongly dependent on the organic moiety.22 The multiplex detection capability of the Lns was demonstrated using six different Lns bound to the same ligand (Ld-33Es). A solution containing 15 μM of the less emissive DyLd-33Es and SmLd-33Es, along with a very low concentration of EuLd-33Es (46 nM) and traces of TbLd-33Es (2.7 nM), was measured in both steady-state and in time-resolved mode. By combining steady-state and time-resolved spectra and by adjusting the detection window of the time-resolved measurements, all four Lns were unambiguously identified (Figures 6b,c, S77). Furthermore, by adding increasing amounts (up to 30 μM and then up to 100 μM) of NdLd-33Es and YbLd-33Es, their distinctive fingerprints in the NIR could be detected in addition to the already observed four visible Lns, thereby proving that six different Lns can be simultaneously detected. Having multiple Ln-complexes in the same solution is not yet flawless. With the increasing number of complexes in the solution, the concentration of the chromophore also increases. This induces an inner-filter effect that lowers the emission intensity of each component in the mixture due to the decreasing intensity of available excitation light (Figures S75 and S76). The chromophore’s total concentration, the different Ln-concentrations, and the Ln-quantum yields and lifetimes are thus important parameters to consider when designing multiplex experiments with Ln-complexes.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.6b11274. Synthesis and characterization of all new compounds, additional photophysical characterization, and detailed discussion of ligand syntheses and complexation procedures (PDF)

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CONCLUSIONS The photophysical properties of 61 Ln-complexes were analyzed. The systematic variation of the sensitizing chromophore has enabled a better understanding of the critical mechanisms promoting or disrupting energy transfer onto the different luminescent Ln-centers. Photoinduced electron transfer from the singlet excited state of the antennae to the Ln(III) ion, resulting in reduction to Ln(II), has been shown to be important, not only for Eu and Yb, but also for Sm and to some extent even for Dy and Nd. Only Gd and Tb are not susceptible to PeT. PeT onto Sm, Dy, and Nd has, to our knowledge, never been observed, and the evidence we have based on fluorescence quenching of the antennae upon Ln-variation that follows the reduction potential of the Ln ions is a crucial finding. Concerning processes resulting in Ln-luminescence, we demonstrated that distant antennae are probably transferring most of the energy by a FRET-type mechanism with limited efficiency, whereas similar chromophores placed within a few ångströms from the Ln-ion display behaviors typical of a classical electron exchange sensitization from the triplet excited state of the ligand. Yb is an exception, as it could be sensitized by PeT. It is worth noting that different sensitization pathways have previously been proposed for two different Ln-ions in the same ligand in some cases.106−109 However, the systematic variation of the ligand structure, in combination with up to six Ln-emitters, has enabled the identification of multiple

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

K. Eszter Borbas: 0000-0003-2449-102X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Swedish Research Council (project grant 2013-4655 for K.E.B.) and Stiftelsen Olle Engkvist Byggmästare (postdoctoral stipends for J.A. and L.S.M.). We thank Ben Johnson and Dr. Hemlata Agarwala for help with the cyclic voltammetry experiments, Ruisheng Xiong for the near-infrared emission measurements, and Prof. Sascha Ott for the critical reading of the manuscript.

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REFERENCES

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