Tuning the photophysical properties of luminescent lanthanide complexes through regioselective antenna fluorination

Abstract

Carbostyrils monofluorinated in the 3, 5, or 6 positions were synthesised from olefinic precursors via a photochemical isomerisation-cyclisation route, and incorporated into octadentate cyclen triacetate ligands that formed luminescent complexes with Tb(III) and Eu(III). The photophysical properties of the emitters were strongly dependent on the position of the fluorination.

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The luminescence of the trivalent lanthanide (Ln) ions is applied in diverse biological and industrial settings ranging from the monitoring of the components of living cells to the thermometric analysis of materials.^1,2 Ln(III) luminescence is often sensitised by a light-harvesting antenna to avoid the need for direct excitation of the Laporte-forbidden 4f–4f transitions.³ Optimisation of energy transfer (EnT) to the Ln(III) and elimination of processes that quench the antenna and Ln(III) excited states are essential for bright emitters.

Photoinduced electron transfer (PeT) from the excited antenna to Ln(III) is feasible for several Lns,^4,5 and for Eu(III) emission it can be an effective luminescence quenching process.⁶ PeT is suppressed when the antenna is less reducing. Antenna substitution with electron-withdrawing groups (e.g. with CF₃, Fig. 1)^4,5 or protonation^7,8 can increase the Eu(III) luminescence quantum yield, but may have unintended consequences on the antenna excited state energies.^5,9,10 Ln sensitisation commonly takes place via the antenna singlet (S₁) and triplet excited states (T₁). Even subtle changes to the antenna may alter the S₁ and T₁ energies and EnT. In the previous examples both antenna trifluoromethylation^4,5 and protonation proved detrimental to Tb(III) emission.⁸

Fig. 1 Decreased PeT quenching of Eu(IIII) luminescence through antenna substitution with electron-withdrawing group(s) (EWG), and its effects on the S₁ and T₁ energies.

Here, we have prepared three monofluorinated 7-aminocarbostyril regioisomers. Electronegative fluorine was expected to decrease PeT by making the antenna less reducing, a strategy that complements the use of C–F bonds to replace the more efficiently quenching C–H oscillators.¹¹ Fluorination has additional potential benefits. Fluorine is a hydrogen isostere conferring metabolic stability, H-bond acceptor ability, and altered lipophilicity on pharmaceuticals.¹² Diagnostic applications of fluorinated probes include multimodal¹³ and responsive¹⁴ systems. ¹⁹F-MRI is a promising low-background technique,¹⁵ and ¹⁸F is an attractive PET label.^16,17

Fluorinated carbostyrils were incorporated into do3a (1,4,7,10-tetraazacyclododecane-1,4,7-triacetate)-based octadentate ligands to enable comparison with previously reported structures.^4,5 The Eu(III), Tb(III), and Gd(III) chelates of the ligands were characterised using ¹H NMR spectroscopy, cyclic voltammetry, and UV-vis absorption and steady-state and time-resolved emission spectroscopies. Our results show fluorination meaningfully impacts the antenna and Ln(III) photophysical properties, and substitution at a remote antenna position could even influence the excited state behaviour of the Ln(III).

Fluorinated antennae were synthesised as shown in Scheme 1 and Schemes S1–S6 (ESI†). The procedures were robust, scalable (e.g. 466 mg of CS^6F was obtained in one experiment), and reproducible. Olefins 5^F were prepared from commercially available starting materials as the Z isomers with excellent selectivity due to the steric clash between the ester group and the aromatic ring.¹⁸ The stereochemical assignment was based on the ³J_HF = 33–38 Hz and ³J_HH = 15–16 Hz coupling constants. The key photochemical olefin isomerisation-cyclisation was carried out by irradiating a 100 mM solution of 5 in MeOH or EtOH with 254 nm-UV light, giving CS^3F, CS^5F, and CS^6F in good to excellent yield. Regioisomer identities were confirmed by 1D and 2D NMR spectroscopy and single-crystal X-ray crystallography (Fig. S1–S6 and Tables S1–S3, ESI†). The analogous CS^4F could not be accessed via similar routes due to the instability of the intermediates (Schemes S3–S5, ESI†). CS/CS^F was acetylated with Ac₂O or chloroacetyl chloride to yield reference compounds AcCS/AcCS^F, or the reactive antennae 6, respectively. 6 were incorporated into LnL (Ln = Gd, Eu, Tb) using procedures previously developed for similar compounds. Synthetic details, compound characterisations, and the attempted syntheses of CS^4F are given in the ESI.† Analytical data were fully consistent with the assigned structures.

Scheme 1 Preparation of CS^F, AcCS, AcCS^F, and LnL^F.

Solution structures of EuL^F were studied by paramagnetic ¹H and ¹⁹F NMR spectroscopy. In CD₃OD at r.t. the ¹H NMR spectra of EuL^3F, EuL^5F, EuL^6F, and EuL^H, were similar (Fig. S7–S10, ESI†). The major isomer had square antiprismatic geometry (4 peaks at >32 ppm). Trace amounts of the twisted square antiprismatic isomer were also present (signals at 12–16 ppm). ¹⁹F NMR spectra supported this interpretation, showing a single peak at −133.8, −118.8, and −134.1 ppm for EuL^3F, EuL^5F, and EuL^6F, respectively (Fig. S11–S13, ESI†). These data are consistent with the ligands imposing similar geometries on the Ln(III) ions in solution in the ground state, and is similar to what has been observed for other do3a-complexes carrying carbostyril antennae.⁶ This was expected as fluorine is small, and the fluorination sites are quite distant from the Ln(III).

The photophysical properties of CS and CS^F were recorded in acetonitrile due to their low aqueous solubility. The lowest-energy bands in the absorption spectra were assigned to π–π* transitions, and were located at 320–360 nm with λ_max = 335, 332, and 339 nm for CS^3F, CS^5F, and CS^6F, respectively (Fig. S18–S22, ESI†), non-fluorinated CS had λ_max = 337 nm. CS, CS^3F, CS^5F, and CS^6F excitation at λ_max resulted in fluorescence emission maxima at λ_em = 384, 400, 387, and 382 nm, respectively (Table 1 and Fig. S23–S27, ESI†). CS^3F had the highest fluorescence quantum yield, Φ_L = 56%. Fluorination in the 5-position had minimal effect on Φ_L compared to CS (Φ_L = 25 and 27%, respectively), while substitution in the 6-position lowered Φ_L to 10%. CS^F fluorescence lifetimes (τ_fl) mirrored the observations made for Φ_L (Table 1). CS^3F had the longest τ_fl (2.84 ns), and CS^6F the shortest, τ_fl = 0.41 ns. CS and CS^5F had very similar τ_fl, 1.15 and 1.09 ns, respectively (Table S5 and Fig. S49–S56, ESI†).

Table 1 Photophysical properties of CS, CS^F,^a and GdL^Fb

	λ max (nm)	λ em (nm)	S 1 (cm^−1)	T 1 (cm^−1)	Φ L (%)	τ fl (ns)
a In acetonitrile at 10 μM concentration. b In aqueous PIPES buffer (10 mM), pH 6.5, at 10 μM complex concentrations. c λ ex = 332 nm (CS^3F), 331 nm (CS^5F), 338 nm (CS^6F), 335 nm (GdL^6F), 327 nm (GdL^5F), 325 nm (GdL^3F). d Calculated from the 0–0 transitions of the Gd-complexes recorded at 77 K. e Relative to quinine sulfate (Φ = 0.59) in H2SO4 (0.05 M).^23
CS	337	384	—	—	27	1.15 (5)
CS^3F	335	400	—	—	56	2.84 (6)
CS^5F	332	387	—	—	25	1.09 (2)
CS^6F	339	382	—	—	10	0.41 (6)
GdL^H	330	369	28 700	22 500	7.6	0.34 (3)
GdL^3F	325	364	29 200	22 100	13	0.60 (5)
GdL^5F	327	367	28 900	22 400	6.1	0.44 (8)
GdL^6F	337	380	28 100	22 300	5.9	0.36 (4)

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LnL absorption spectra were collected in aqueous solutions (0.01 M PIPES buffer, pH = 6.5). Absorption maxima were blue-shifted relative to the corresponding CS with λ_max = 325, 327, 337, and 330 nm for LnL^3F, LnL^5F, LnL^6F, and LnL^H, respectively (Fig. 2 and Fig. S28–S32, ESI†).

Fig. 2 Normalised absorption (grey, 298 K), excitation [blue, λ_em = 380 nm (GdL^6F), λ_em = 364 nm (GdL^3F), λ_em = 546 nm (Tb), λ_em = 615 nm (Eu), 298 K], steady-state emission at 298 K [black, λ_ex = 335 nm (LnL^6F), λ_ex = 325 nm (LnL^3F)], steady-state emission at 77 K [purple, λ_ex = 335 nm (LnL^6F), λ_ex = 325 nm (LnL^3F)] and time-resolved emission [green (Tb), red (Eu), λ_ex = 335 nm (LnL^6F), λ_ex = 325 nm (LnL^3F), 298 K] spectra of LnL^F.

Gd(III) excited states are too high to accept energy from the antennae, therefore, GdL are useful for determining the antenna photophysical properties in LnL without interference from photo- or redox-active Ln(III). Carbostyril excitation in GdL returned antenna fluorescence that was blue-shifted and less intense than that of the corresponding 7-aminocarbostyril (Fig. S33–S36, ESI†). Φ_L was largest for GdL^3F (13%) and smallest for GdL^6F (5.9%), with Φ_L(GdL^5F) = 6.1% and Φ_L(GdL^H) = 7.6% in between. Steady state emission spectra were recorded at 77 K to determine the antenna T₁ (Fig. S45–S48, ESI†). Notably, fluorination in all three investigated positions lowered the antenna T₁ from 22 500 cm⁻¹ in GdL^H. GdL^3F had the lowest energy T₁ (22 100 cm⁻¹), and GdL^5F had the highest, at only 300 cm⁻¹ higher energy. These are small but impactful differences. The ⁵D₄ emitting level of Tb(III) is located at 20 400 cm⁻¹, and the antenna T₁ must be at least ∼2000 cm⁻¹ higher energy to avoid thermal back energy transfer (BET). Thus, TbL^3F and possibly even TbL^6F (but likely not TbL^5F) may be susceptible to BET. Tb(III) complexes that undergo BET are oxygen sensitive, and are useful for O₂-sensing and cytotoxic singlet oxygen generation.^19,20 T₁ are ∼5000 cm⁻¹ higher than the emissive ⁵D₀ level of Eu(III), which is suitable for Eu(III) sensitization.²¹ T₁ in LnL^F are closer to the accepting ⁵D₂ Eu(III) level (21 500 cm⁻¹) than in LnL^H, which may result in better energy transfer in the fluorinated complexes.^21,22

Excitation of TbL and EuL at λ_max yielded green and red Ln(III) luminescence, respectively (Fig. 2 and Fig. S37–S44, ESI,†Table 2), with residual antenna fluorescence. TbL had slightly lower Φ_L than the analogous GdL likely due to some antenna S₁-mediated EnT to Tb(III).⁶EuL had drastically diminished Φ_L, which may be due to a combination of EnT from S₁, and depopulation of S₁ by PeT. AcCS^F oxidation potentials (E_ox) were found by cyclic voltammetry as +1.73, +1.86, and +1.77 V (vs. NHE, for AcCS^3F, AcCS^5F, AcCS^6F, respectively); only 5-fluorination made antenna oxidation more difficult than in AcCS (E_ox = +1.81 V). PeT was calculated to be slightly less thermodynamically favoured in EuL^5F, and EuL^6F than in EuL^H, and more favoured in EuL^3F (ΔG(PeT) = −1.01, −1.14, −0.98, and −0.97 eV, for EuL^H, EuL^3F, EuL^5F, and EuL^6F, respectively (see ESI† for details)). Thus, the effects of fluorination on the antenna S₁, T₁ and E_ox, and in turn on ΔG(PeT) can be difficult to predict.

Table 2 Photophysical properties of LnL^F (Ln = Eu, Tb),^a and τ_rad, Φ^Ln_Ln, and η_sensEuL^Fb

	Φ L (%)	τ fl (ns)	Φ Ln (%)	τ rad (ms)	Φ ^LnLn (%)	η sens (%)
a [LnL] = 10 μM in 10 mM PIPES buffered H2O, pH 6.5. b Determined using the method in ref. 26.Itot/IMD: integral ratio of total Eu-centred corrected emission spectrum (570–800 nm) and ^5D0 → ^7F1 band (582–603 nm), AMD,0 = 14.65 s^−1, n = 1.333 (refractive index),^27τobs = τH2O. c Relative to quinine sulfate (Φ = 0.59) in H2SO4 (0.05 M).^23 d In parentheses: compared to GdL analogue. e Biexponential fit better based on χ^2. f Too short to measure. g Calculated from the steady-state emission spectra. h Calculated from the time-resolved emission spectra.
TbL^H	5.1 (67%)	0.21(4)	22.5	—	—	—
TbL^3F	8.1 (63%)	0.39(2)	5.6	—	—	—
TbL^5F	4.6 (75%)	0.36(3)	21.7	—	—	—
TbL^6F	4.6 (78%)	0.25(4), 2.40(3)^e	16.7	—	—	—
EuL^H	0.261 (3.4%)	—^f	4.34	5.18^g, 4.73^h	11.9^g, 13.1^h	36.2^g
EuL^3F	0.680 (5.3%)	0.93(6), 0.42(5)^e	1.09	9.25^g, 5.10^h	6.7^g, 12.3^h	16.1^g
EuL^5F	0.814 (13%)	0.47(6), 1.76(5)^e	5.05	5.25^g, 5.11^h	11.5^g, 11.8^h	43.4^g
EuL^6F	0.207 (3.5%)	0.20(1), 2.85(5)^e	5.10	5.28^g, 5.19^h	11.6^g, 11.8^h	43.8^g

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The Ln(III) luminescence lifetimes (τ_H2O) were measured by time-resolved emission spectroscopy. The decays were monoexponential. τ_H2O values varied for Ln = Tb but were almost identical for all EuL (∼0.61 ms) (Table S4, ESI†). The number of Ln(III)-bound water molecules (q) were q = 1 for EuL. Deviations for TbL from q = 1 could be due to BET, which makes this method inapplicable,^24,25 or the result of the typical error of q ±0.5.

TbL^5F and TbL^H had the highest Tb-centred luminescence quantum yields (Φ_Ln = 21.7% and 22.5%, respectively, values identical within experimental error). The low Φ_Ln of TbL^3F is presumably the result of BET. EuL^5F and EuL^6F had Φ_Ln ∼5%, which is higher than most Eu(III) complexes with similar structures, i.e. uncharged do3a-based emitters with secondary amide-linked carbostyril antenna, including EuL^H (Φ_Ln = 4.34%). EuL^3F, however, had low Φ_Ln = 1.09%. Unlike TbL^3F, EuL^3F does not suffer from BET, therefore, an alternative explanation for the poor performance of this emitter was necessary.

Φ _Ln is the product of the intrinsic quantum yield of the Ln(III) (ϕ^Ln_Ln) and the Ln(III) sensitisation efficiency (η_sens, eqn (1)), i.e. the efficiency of Ln(III) excited state population. For Eu(III) ϕ^Ln_Ln can be determined from the corrected emission spectrum.²⁶

In EuL^5F and EuL^6Fη_sens is increased compared to EuL^H, presumably due to a combination of the small adjustments in spectral overlap and PeT quenching. EuL^3F had markedly lower η_sens and ϕ^Ln_Ln than the other EuL (Table 2). The steady-state and time-resolved EuL^3F emission spectra have different shapes. Eu(III) spectra are sensitive to coordination environment, and these differences indicate the presence of several emissive species.²¹ The signal of the slow-decaying component dominating the time-resolved spectrum resembles the EuL^5F/EuL^6F/EuL^H spectra. Contribution from the fast-decaying species modifies the steady-state EuL^3F spectrum. If τ_obs is assumed unchanged, the steady-state spectral shape yields a lower overall ϕ^Ln_Ln (Table 2). The spectrum of TbL^3F is similarly time-dependent, but not those of Eu/TbL^5F and Eu/TbL^6F. The reasons for the diminished η_sens of EuL^3F are unclear. PeT is more favoured in EuL^3F than in EuL^5F and EuL^6F, and EuL^F have much lower Φ_L than the corresponding GdL^F, which is consistent with PeT quenching. The τ_fl of EuL^F and GdL^F, however, cannot be compared directly. The biexponential decay of the EuL^F antenna fluorescence suggested the presence of additional emitters to those seen in GdL^F. Further work is therefore needed to understand the effect of fluorination on EnT and PeT.

In conclusion, monofluorinated 7-aminocarbostyrils, obtained via a photochemical cyclisation, were competent sensitisers of Eu(III) and Tb(III) emission. The position of the fluorine had a dramatic impact on the antenna and Ln(III) photophysical properties, rendering the emission oxygen-sensitive (TbL^3F, TbL^4F), and increasing (EuL^5F, EuL^6F), or decreasing Φ_Ln, (TbL^3F, TbL^6F, EuL^3F) compared to non-fluorinated LnL^H. 5-Fluorination improved Eu(III) emission without negatively impacting Tb(III) luminescence. Remote fluorination influenced the excited-state behaviour of LnL^3F. Work towards the 4-fluorinated isomer, and ligands containing other EWGs than fluorine is ongoing.

D. K. did all experiments except the crystallographic analysis, which was done by A. O. K. E. B. designed the project, secured funding, and supervised the work. All authors contributed to data analysis and manuscript writing.

This work was funded by Knut och Alice Wallenbergs Stiftelse (Dnr: 2018.0066) and Vetenskapsrådet (2021-04625). We thank Eirini Servetas for help with the synthesis, and Salauat R: Kiraev for the critical reading of the manuscript.

Conflicts of interest

There are no conflicts to declare.

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Footnote

† Electronic supplementary information (ESI) available: Synthesis, characterisation, and NMR spectra of all new compounds, additional crystallographic, photophysical, and electrochemical characterisation. CCDC 2155036–2155038. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2cc01229d

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