Eu(iii) and Tb(iii) complexes of 6-fold coordinating ligands showing high affinity for the hydrogen carbonate ion: A spectroscopic and thermodynamic study

Article abstract of DOI:10.1039/c8dt03621g

In the present contribution, four classes of Ln(iii) complexes (Ln = Eu and Tb) have been synthesized and characterized in aqueous solution. They differ by charge, Ln(bpcd)⁺ [bpcd^2- = N,N′-bis(2-pyridylmethyl)-trans-1,2-diaminocyclohexane N,N′-diacetate] and Ln(bQcd)⁺ (bQcd^2- = N,N′-bis(2-quinolinmethyl)-trans-1,2-diaminocyclohexane N,N′-diacetate) being positively charged and Ln(PyC3A) (PyC3A^3- = N-picolyl-N,N′,N′-trans-l,2-cyclohexylenediaminetriacetate) and Ln(QC3A) (QC3A^3- = N-quinolyl-N,N′,N′-trans-l,2-cyclohexylenediaminetriacetate) being neutral. Combined DFT, spectrophotometric and potentiometric studies reveal the presence, under physiological conditions (pH 7.4), of a couple of equally and highly stable isomers differing by the stereochemistry of the ligands (trans-N,N and trans-O,O for bpcd^2- and bQcd^2-; trans-O,O and trans-N,O for PyC3A^3- and QC3A^3-). Their high logβ values (9.97 < logβ < 15.68), the presence of an efficient antenna effect and the strong increase of the Ln(iii) luminescence intensity as a function of the hydrogen carbonate concentration in physiological solution, render these complexes as very promising optical probes for a selective detection of HCO₃^-in cellulo or in extracellular fluid. This particularly applies to the cationic Eu(bpcd)⁺, Tb(bpcd)⁺ and Eu(bQcd)⁺ complexes, which are capable of guesting up to two hydrogen carbonate anions in the inner coordination sphere of the metal ion, so that they show an unprecedented affinity towards HCO₃^- (logK for the formation of the adduct in the 4.6-5.9 range).

Full text of DOI:10.1039/c8dt03621g

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Eu(III) and Tb(III) complexes of 6-fold coordinating
ligands showing high affinity for the hydrogen
carbonate ion: a spectroscopic and
thermodynamic study†
Cite this: DOI: 10.1039/c8dt03621g
b
Fabio Piccinelli, *a Chiara De Rosa,a Andrea Melchior, *b Georgina Faura,
a
Marilena Tolazzib and Marco Bettinelli
In the present contribution, four classes of Ln(III) complexes (Ln = Eu and Tb) have been synthesized and
characterized in aqueous solution. They differ by charge, Ln(bpcd)+ [bpcd2− = N,N’-bis(2-pyridylmethyl)-
trans-1,2-diaminocyclohexane N,N’-diacetate] and Ln(bQcd)+ (bQcd2− = N,N’-bis(2-quinolinmethyl)-
trans-1,2-diaminocyclohexane N,N’-diacetate) being positively charged and Ln(PyC3A) (PyC3A3−
=
N-picolyl-N,N’,N’-trans-l,2-cyclohexylenediaminetriacetate) and Ln(QC3A) (QC3A3− = N-quinolyl-N,N’,
N’-trans-l,2-cyclohexylenediaminetriacetate) being neutral. Combined DFT, spectrophotometric and
potentiometric studies reveal the presence, under physiological conditions (pH 7.4), of a couple of
equally and highly stable isomers differing by the stereochemistry of the ligands (trans-N,N and trans-O,O
for bpcd2− and bQcd2−; trans-O,O and trans-N,O for PyC3A3− and QC3A3−). Their high log β values
(9.97 < log β < 15.68), the presence of an efficient antenna effect and the strong increase of the Ln(III)
luminescence intensity as a function of the hydrogen carbonate concentration in physiological solution,
−
render these complexes as very promising optical probes for a selective detection of HCO3 in cellulo or
in extracellular fluid. This particularly applies to the cationic Eu(bpcd)+, Tb(bpcd)+ and Eu(bQcd)+ com-
Received 7th September 2018,
Accepted 7th November 2018
plexes, which are capable of guesting up to two hydrogen carbonate anions in the inner coordination
−
DOI: 10.1039/c8dt03621g
sphere of the metal ion, so that they show an unprecedented affinity towards HCO3 (log K for the
rsc.li/dalton
formation of the adduct in the 4.6–5.9 range).
absorbance below 0.1 at the excitation wavelength, the inten-
sity of the luminescence signal of the complexes is pro-
Introduction
Eu(III) and Tb(III) complexes have been broadly exploited as portional to their concentration over a wide range of values.
efficient optical probes in the field of bioimaging and With this in mind, lanthanide-based molecular probes have
sensing1–6 due to the peculiar properties of their f ↔ f tran- been employed for the detection of the pH7 and intracellular
sitions, such as long luminescence lifetime and large energy analytes such as ATP.8 The optical properties of the complexes
difference between the absorbing and emissive states. These are strongly dependent on the nature of the ligand; the
advantageous properties allow the mitigation of the inter- luminescence stemming from the metal ion can be con-
ference of background fluorescence originating from the bio- veniently sensitized if the ligand is capable of strongly absorb-
logical sample and the removal of self-absorption issues, ing and efficiently transferring the UV excitation to the metal
respectively. Thanks to both the lack of self-absorption and the ion (antenna effect). Furthermore, solvent molecules usually
usual low concentration of the optical probe, which ensures give rise to competitive non-radiative mechanisms such as the
multiphonon relaxation process. On the basis of the “energy
gap law”, if the gap between the emitting level and the one
aLaboratorio Materiali Luminescenti, DB, Università di Verona, and INSTM,
UdR Verona, Strada Le Grazie 15, 37134 Verona, Italy.
E-mail: fabio.piccinelli@univr.it
bDipartimento Politecnico di Ingegneria e Architettura, Laboratorio di Tecnologie
Chimiche, Università di Udine, via Cotonificio 108, 33100 Udine, Italy.
E-mail: andrea.melchior@uniud.it
below is bridged by less than four vibrational quanta, the
multiphonon relaxation process significantly works and the
luminescence quantum yield will be low.9,10 The high energy
of the O–H vibrations in water molecules is particularly
efficient in the non-radiative quenching of the emitting level
and this phenomenon is especially relevant for applications in
biomedicine, where aqueous media are commonly employed.
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8dt03621g
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Nevertheless, Eu(III) and mainly Tb(III) are less affected by the
multiphonon relaxation process as the energy gap between the
emitting level and the lower lying ones is relatively large [about
12 400 cm−1 for Eu(III) and 14 800 cm−1 for Tb(III)].11
As far as optical sensing experiments based on luminescent
lanthanide complexes are concerned, the displacement of
water molecules from the inner coordination sphere of the
metal ion by the target molecule is often employed. This dis-
placement gives rise to an increase in the quantum yield and
the concomitant increase in the luminescence intensity could
be linked to the concentration of the analyte in solution.
Another important factor that must not be neglected when
the compounds are used in in vitro experiments is the impact
of the hydrophobicity and charge of lanthanide metal com-
plexes on cell viability and cell association,12 including their
membrane permeability.13–17 The in vitro localization of the
optical probe affects the type of analyte that can be detected.
For example, a probe with an extracellular location is particu-
larly suitable to detect analytes such as group I ions, polysac-
charides, hormones, or other signaling molecules.12
Another crucial aspect to consider is the selectivity of the
optical response towards a particular analyte. In this context,
the modulation of the structure of the side pendants within
the DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-triacetate)-
based complexes gave the best results when serum proteins
and biologically relevant ions are taken into account.18–21
In summary, the charge and lipophilicity of the probe and
selectivity towards a particular target analyte are crucial pro-
perties that must be considered when designing a complex
with potential application in optical sensing of biologically
relevant species. As a natural extension of a recent structural
and spectroscopic study, performed by some of us, on a prom-
ising chiro-optical probe based on a Tb(III) complex of a polya-
minocarboxylate ligand [N,N′-bis(2-pyridylmethyl)-trans-1,2-
diaminocyclohexane-N,N′-diacetic acid (H2bpcd)],18,19 we
propose a new library of ligands and their relative Eu(III) and
Tb(III) complexes, based on the chiral diaminocyclohexane
(DACH) motif (Fig. 1).22–25
The proposed water-soluble complexes differ: (i) by charge,
since Ln(bpcd)+ and Ln(bQcd)+ are cationic whilst Ln(PyC3A)
and Ln(QC3A) are neutral, (ii) by steric hindrance at the metal
ion, which is large in the case of Ln(bQcd)+ and small in the
case of Ln(PyC3A) and (iii) by lipophilicity, the molecules con-
taining the quinoline fragment being more hydrophobic than
the relative pyridine-based ones. Total charge and steric hin-
drance are expected to have a strong impact on the stability of
both the complexes and their adducts with target analytes so as
to enable the opportunity of a selective probe–target interaction.
Fig. 1 Library of the complexes presented in this contribution:
Ln(bQcd)+ and Ln(bpcd)+ are cationic complexes; Ln(QC3A) and
Ln(PyC3A) are neutral complexes. The solvent molecules bound to the
metal ion are omitted for the sake of clarity.
gen carbonate (HCO3−) also meets this requirement and, in
addition, plays a crucial role in many physiological processes26
including intracellular pH homeostasis, kidney function and
sperm maturation, and therefore must be considered an impor-
−
tant target in probe development. Moreover, the HCO3 concen-
tration is critical in assessing metabolic acidosis, that is abnor-
mally increased hydrogen ion concentration. Patients with
chronic kidney disease due to metabolic acidosis show low
serum hydrogen carbonate concentrations.27,28 For all these
reasons, in the present contribution we present the synthesis,
optical spectroscopy, the thermodynamic and structural charac-
terization in aqueous solution of the Eu(III) and Tb(III) complexes
as shown in Fig. 1. The good performance of these molecules in
the optical detection of hydrogen carbonate anions under physio-
logical conditions is also documented and analyzed in relation to
the aforementioned properties of the complexes (i.e. total charge,
steric hindrance, etc.).
Experimental section
In addition, in light of the lower number of donating atoms All commercially available reagents were used as received from
(6-fold coordination) for ligands shown in Fig. 1 than in the case their respective suppliers. Solvents (Sigma-Aldrich) were dried
of ligands commonly employed for Ln(III)-based luminescence when required using an appropriate drying agent. Reactions
anion sensing (i.e. DOTA-like possessing 8-fold coordination), we requiring anhydrous conditions were carried out using
expect a higher number of target analyte molecules bound to the Schlenk-line techniques under an atmosphere of dry argon.
metal ion and a concomitant higher affinity towards them. This Water and H2O refer to high purity water obtained from the
should be particularly true when non-sterically demanding ‘Millipore Elix 10’ purification system. Eu(CF3SO3)3 and
anions are considered. Together with monoatomic anions, hydro- TbCl3·6H2O (Aldrich, 98%) were stored under vacuum for
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several days at 80 °C and then transferred to a glove box. All for C30H38N6O4 (MW 546.7): C, 65.91; H, 7.01; N, 15.37; O,
other chemicals were purchased from Alfa Aesar.
11.71 found: C, 65.79; H, 7.09; N, 15.27; O, 11.59.
Thin-layer chromatography was carried out on neutral
The triflate of the cationic complex Eu(bQcd) (complex 4)
alumina plates (Fluka Analytical) or silica plates (Sigma- has been synthesized as follows: ligand
3 (100 mg,
Aldrich) and visualized under a UV lamp (254 nm). Cationic 0.182 mmol) was dissolved in hot (60 °C) 2-propanol (7 ml).
exchange chromatography was performed on SCX cartridges Upon cooling, 98% europium(III) trifluoromethanesulfonate
(1 g) purchased from “Agilent Technologies-sample Prep (109 mg, 0.182 mmol) was added portion-wise, and a yellowish
solutions”.
suspension was formed. After neutralization with 2 M aq KOH
(pH ≈ 7), the reaction mixture was stirred at room temperature
for 2 h. The suspension was centrifuged, and the solid
collected was suspended in methanol (5 ml). The resulting
N,N′-Bis(2-quinolinmethyl)-trans-1,2-diaminocyclohexane
N,N′-tert-butyl diacetate (1R,2R) (2)
Ligand 1 (1.8 g, 4.54 mmol) was dissolved in a mixture of solid was removed by centrifugation, and the filtrate was con-
anhydrous acetonitrile (80 mL) and anhydrous potassium car- centrated under reduced pressure to give 44 mg of the desired
bonate under inert conditions (argon). Then, a solution of tert- product as a beige solid (yield: 30%). UV-Vis spectroscopy:
butyl 2-bromoacetate (1.68 ml, 11.4 mmol) in anhydrous aceto- ε (319 nm): 8808 M−1 cm−1 (water). Elemental anal. calc. for
nitrile (15 mL) was added dropwise over ten minutes. After stir- C31H30EuF3N4O7S·(H2O)2 (MW 847.6): C, 43.93; H, 4.04; N,
ring for 12 h at room temperature dichloromethane was added 6.61; O, 16.99; S, 3.78 found: C, 43.87; H, 4.00; N, 6.48; O,
and the reaction mixture was washed with brine solution. The 17.04; S, 3.89.
organic phase was evaporated under reduced pressure to give
3.3 g of a yellowish oil. The crude product was purified by
chromatography on activated neutral alumina (Al2O3,
{2-[(Pyridyl-2-ylmethyl)-amino]-cyclohexyl}-carbamic acid tert-
butyl ester 6 and {2-[(quinolyl-2-ylmethyl)-amino]-cyclohexyl}-
carbamic acid tert-butyl ester 10
Cy : AcOEt from 9 : 1 to 1 : 9) giving 2.50 g of a yellowish oil
(yield: 88%). 1H-NMR (CDCl3) δ (ppm) 8.07–8.04 (m, 4H, quino- Compound 5 (0.670 g, 3.13 mmol) was added to a solution of
line), 7.92 (d, J = 7.76 Hz, 2H, quinoline), 7.75 (d, J = 7.10 Hz, 2-quinolinecarboxaldehyde
or
2-pyridinecarboxaldehyde
2H, quinoline), 7.69 (7, J = 7.68 Hz, 2H, quinoline), 7.50 (t, J = (3.13 mmol) in ethanol (35 ml) and stirred at room tempera-
7.40 Hz, 2H, quinoline), 4.16 (m, 2H, methylene-ester), 3.86 (d, ture for 12 h. Sodium borohydride was slowly added to the
JGEM = 13.75 Hz, 2H, methylene-ester), 3.49 (d, JGEM = 17.22 Hz, mixture. The reaction was monitored by TLC (SiO2,
2H, methylene-quinoline), 3.31 (d, JGEM = 17.22 Hz, 2H, methyl- cyclohexane : ethyl acetate 7 : 3 + NH4OH 30% w/w) and after
ene-quinoline), 2.71 (m, 2H, methylene-cyclohexane), 2.18–1.12 4 h the mixture was extracted twice with dichloromethane and
(m, 8H, cyclohexane), 1.46 (s, 18H). 13C-NMR (CDCl3) δ (ppm) the solvent was removed under reduced pressure to give
173.0, 159.3, 148.5, 135.3, 129.4, 129.0, 127.1, 125.8, 125.0, respectively compounds 6 and 10 as yellowish oils, in quanti-
122.0, 73.5, 57.8, 55.1, 53.7, 29.2, 26.7, 22.0. Elemental anal. tative yield, which were used in the next step without further
calc. for C38H48N4O4 (MW 624.8): C, 73.05; H, 7.74; N, 8.97; O, purification.
10.24 found: C, 72.89; H, 7.51; N, 9.03; O, 10.36.
N-Pyridyl-2-ylmethyl-cyclohexane-1,2-diamine (7) and
N,N′-Bis(2-quinolinmethyl)-trans-1,2-diaminocyclohexane
N,N′-diacetic acid (1R,2R) (H2bQcd, ligand 3 as ammonium salt)
N-quinolyl-2-ylmethyl-cyclohexane-1,2-diamine (11)
Compound 6 or 10 (3.13 mmol) was added to a trifluoroacetic
2 (1.20 g, 1.92 mmol) was dissolved in aq HCl (6 M, 30 ml); acid 98% w/w (13 ml) and dichloromethane (40 ml) solution
the obtained reaction mixture was stirred for 12 h at 80 °C. and stirred at room temperature for 12 h. The solvent was
The reaction mixture was washed with ethyl acetate and the removed under reduced pressure, and the obtained trifluoro-
aqueous phase was evaporated under reduced pressure. The acetate salt (≈3 g) was purified by cationic exchange chromato-
obtained brownish oil (2.47 g) was suspended in 10 ml of graphy (eluent: NH3 3 M in MeOH) to give 398 mg (yield 61%)
methanol, aqueous ammonia solution was added until pH 8–9 of ligand 11. 1H-NMR (CDCl3) δ (ppm) 8.13 (d, J = 8.33 Hz,
was reached and 1.05 g of a yellowish solid were obtained after 1H), 8.08 (d, J = 8.56 Hz, 1H), 7.81 (d, J = 8.33 Hz, 1H), 7.71 (t,
chromatography [C18 column; eluent H2O : acetonitrile 4 : 6 + J = 7.74 Hz, 1H), 7.55–7.48 (m, 2H), 4.25 (dd, JGEM = 14.55 Hz,
0.1% aq NH4OH 30% w/w (50 ml)]. This solid was further puri- 1H), 4.07 (dd, JGEM = 14.55 Hz, 1H), 3.71 (m, 1H), 2.50 (m, 1H),
fied by trituration in DCM : AcOEt : EtOH 1 : 2 : 2 at 80 °C for 2.18 (m, 2H), 1.92 (m, 1H), 1.75 (m, 1H), 1.70 (m, 1H),
30 minutes, obtaining 548 mg of a yellowish solid (ligand 3, 1.35–1.04 (m, 5H). 13C-NMR (CDCl3) δ (ppm) 160.2, 148.2,
yield: 52%). UV-Vis absorption spectroscopy (water : methanol 135.4, 129.0, 128.8, 127.3, 126.1, 125.1, 122.1, 57.1, 53.2, 52.1,
1
9 : 1): ε (316 nm): 6728 M−1 cm−1. H-NMR (CD3OD) δ (ppm) 31.4, 28.9, 22.3. Elemental anal. calc. for C16H21N3 (MW 255.4):
8.05–7.48 (m, 12H, quinoline), 3.74–3.55 (m, 8H, methylene- C, 75.26; H, 8.29; N, 16.46 found: C, 75.21; H, 8.22; N, 16.39.
1
ester/quinoline), 2.39 (m, 2H, cyclohexane), 1.98 (m, 2H, cyclo-
Compound 7: Yield 38%. H-NMR (CDCl3) δ (ppm) 8.52 (m,
hexane), 1.67–1.28 (m, 6H, cyclohexane). 13C-NMR (CD3OD) δ 1H), 7.62 (t, J = 7.54 Hz, 1H), 7.34 (d, J = 7.70 Hz, 1H), 7.13 (t,
(ppm) 171.4, 160.1, 146.6, 137.3, 129.7, 127.9, 127.6, 126.7, J = 5.90 Hz, 1H), 4.03 (dd, JGEM = 14.09 Hz, 1H), 3.83 (dd,
126.3, 121.2, 61.6, 56.1, 53.4, 24.5, 24.1. UV-Vis spectroscopy: ε JGEM = 14.09 Hz, 1H), 3.64 (m, 1H), 2.43 (m, 1H), 2.18 (m, 2H),
(316 nm) = 6248 M−1 cm−1 (methanol). Elemental anal. calc. 1.88 (m, 1H), 1.75 (m, 1H), 1.70 (m, 1H), 1.35–1.04 (m, 5H).
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13C-NMR (CDCl3) δ (ppm) 159.5, 149.0, 136.0, 123.5, 120.6, pressure and the crude product was purified by ionic exchange
57.8, 52.1, 31.5, 29.4, 22.3, 21.5. Elemental anal. calc. for chromatography to give the corresponding product 9 or 13
C12H19N3 (MW 205.3): C, 70.20; H, 9.33; N, 20.47 found: C, (yield = 24% for 9 and 40% for 13). Compound 9: ESI-MS (scan
70.15; H, 9.19; N, 20.44.
ES+; m/z): 468 (100%); 469 (20%) ([Na4(PyC3A)]+). Elemental
anal. calc. for C18H34N6O6 (MW 430.5): C, 50.22; H, 7.96; N,
19.52; O, 22.30 found: C, 50.18; H, 7.90; N, 19.47; O, 22.18.
Compound 13: ESI-MS (scan ES+; m/z): 513 (100%); 514
(25%) ([(NH4)Na3(QC3A)]+). Elemental anal. C22H36N6O6 (MW
N-Picolyl-N,N′,N′-trans-l,2-cyclohexylenediamine-tert-butyl
triacetate (8) and N-quinolyl-N,N′,N′-trans-l,2-
cyclohexylenediamine-tert-butyl triacetate (12)
Under an inert atmosphere, compound 7 or 11 (1.94 mmol, 480.6): C, 54.99; H, 7.55; N, 17.49; O, 19.98 found: C, 54.90; H,
1.20 mmol, respectively) was dissolved in an anhydrous aceto- 7.46; N, 17.42; O, 20.01.
nitrile (40 ml or 25 mL) solution of N,N-diisopropylethylamine
Eu(PyC3A) (14a) [and Tb(PyC3A) (14b)] has been syn-
(6.8 mmol or 4.19 mmol,). Then, tert-butyl 2-bromoacetate thesized as follows: ligand 9 (60 mg, 0.140 mmol) was partially
(6.8 mmol or 4.19 mmol) in anhydrous acetonitrile (10 mL or dissolved in a mixture of 2-propanol : ethanol 1 : 1 (4 ml) by
5 mL) was added dropwise. The reaction was monitored using heating at ≈60 °C. Then, 98% europium(III) trifluoromethane-
TLC (SiO2, Rf: 0.47, DCM : MeOH 95 : 5 + 0.5% NEt3) and after sulfonate (83.6 mg, 0.140 mmol) was added portion-wise and
12 h, water (approx. 25 mL) was added and the reaction mixture the pH of the solution was carefully adjusted to 7 by the
was extracted twice with dichloromethane. The combined addition of 2 M aq KOH. The obtained suspension was stirred
organic phases were dried on anhydrous Na2SO4 and the at room temperature for 12 h. The collected solid (≈94 mg)
solvent was evaporated under reduced pressure to give 0.580 g was re-crystallized in methanol (≈10 ml) and Et2O (≈30 ml)
of the crude product which was purified by chromatography (on solution to yield 70 mg (yield 95%) of a whitish solid (14a).
silica gel, DCM/MeOH 95 : 5 + 0.5% triethylamine, Rf: 0.47) UV-Vis spectroscopy: ε (265 nm): 3390 M−1 cm−1 (water).
giving rise to compounds 8 (yield 58%) and 12 (yield = 55%).
ESI-MS (scan ES+; m/z): 552 (100%); 550 (90%) ([NaEu
Compound 8: 1H-NMR (CDCl3) δ (ppm) 9.97 (d, J = 6.56, (PyC3A)]+). Elemental anal. calc. for C18H22EuN3O6·(H2O)2
1H), 8.79 (d, J = 7.91, 1H), 8.34 (t, J = 7.91, 1H), 7.94 (t, J = 6.56, (MW 564.4): C, 38.31; H, 4.64; N, 7.45; O, 22.68 found: C,
1H), 6.30 (dd, JGEM = 17.64 Hz, 1H), 5.94 (dd, JGEM = 17.64 Hz, 38.28; H, 4.54; N, 7.40; O, 22.51.
1H), 4.55 (dd, JGEM = 16.93 Hz, 2H), 3.53 (m, 2H), 3.44 (dd,
Ligand 9 (27 mg, 0.063 mmol) was dissolved in water
JGEM = 16.93 Hz, 2H), 2.66 (m, 3H), 2.08 (m, 2H), 1.78 (m, 2H), (3 ml), then terbium(III) chloride hexahydrate (23.5 mg,
1.45 (s, 27H), 1.12 (m, 3H). 13C-NMR (CDCl3) δ (ppm) 172.4, 0.063 mmol) was added portion-wise and the pH of the solu-
171.0, 170.5, 159.4, 149.4, 136.0, 121.3, 123.0, 72.9, 73.3, 73.5, tion was carefully adjusted to 7 by the addition of 2 M aq KOH.
57.3, 55.5, 55.3, 54.0, 54.2, 30.5, 30.1, 29.4, 27.3, 26.9, 22.2. The obtained solution was stirred at room temperature for
Elemental anal. calc. for C30H49N3O6 (MW 547): C, 65.78; H, 12 h. The solvent was removed under reduced pressure and
9.02; N, 7.67; O, 17.53 found: C, 65.70; H, 8.95; N, 7.73; O, 17.41. the residue was re-crystallized in methanol (≈2 ml) and Et2O
1
Compound 12: H-NMR (CDCl3) δ (ppm) 8.12 (m, 2H), 8.07 (≈15 ml) solution yielding a white solid after centrifugation
(d, 1H), 7.81 (d, J = 7.92, 1H), 7.67 (t, J = 7.71, 1H), 7.51 (t, J = (34 mg of 14b, quantitative yield). UV-Vis spectroscopy:
7.29, 1H), 4.32 (dd, JGEM = 13.79 Hz, 1H), 3.94 (dd, JGEM
=
ε (266 nm): 4008 M−1 cm−1 (water). ESI-MS (scan ES+; m/z):
13.79 Hz, 1H), 3.60 (m, 2H), 3.52 (m, 4H), 2.81 (m, 1H), 2.67 558 (100%) ([NaTb(PyC3A)]+). Elemental anal. calc. for
(m, 1H), 2.15 (m, 1H), 2.09 (m, 1H), 1.74 (m, 2H), 1.45 (s, 27H), C18H22TbN3O6·(H2O)2 (MW 571.3): C, 37.84; H, 4.59; N, 7.35;
1.14 (m, 4H). 13C-NMR (CDCl3) δ (ppm) 173.1, 172.9, 172.1, O, 22.40 found: C, 37.78; H, 4.50; N, 7.30; O, 22.37.
160.2, 148.0, 134.0, 130.3, 127.5, 126.0, 124.7, 123.0, 74.5, 74.1,
Eu(QC3A) (15) has been synthesized as follows: compound
73.3, 58.2, 57.4, 56.0, 55.3, 55.0, 54.1, 33.0, 32.3, 32.1, 28.1, 13 (60 mg, 0.125 mmol) was partially dissolved in a mixture of
27.3, 22.8, 22.1. Elemental anal. calc. for C34H51N3O6 (MW 2-propanol : ethanol 8 : 2 (6 ml) at ≈60 °C. Then, 98%
597.8): C, 68.31; H, 8.60; N, 7.03; O, 16.06 found: C, 68.27; H, Eu(CF3SO3)3 (75 mg, 0.125 mmol) was added portion-wise fol-
8.51; N, 7.00; O, 15.97.
lowed by 2 M aq KOH until pH ≈ 7. The obtained suspension
was stirred at room temperature for 12 h. The solid was removed
under centrifugation, and the solution was dried under reduced
pressure to give ≈112 mg of a white solid, which was re-crystal-
lized in ethanol (≈10 ml) and Et2O (≈40 ml) solution, yielding a
white solid after centrifugation (55 mg; yield 76%). UV-Vis spec-
N-Picolyl-N,N′,N′-trans-l,2-cyclohexylenediaminetriacetic acid
(H3PyC3A, 9 as ammonium salt) and N-quinolyl-N,N′,N′-trans-
l,2-cyclohexylenediaminetriacetic acid (H3QC3A, 13 as
ammonium salt)
Compound 8 or 12 (1.12 mmol, 0.652 mmol, respectively) was troscopy: ε (319 nm) = 3725 M−1 cm−1 (water). ESI-MS (scan
added to an aqueous HCl (6 M, 22 ml or 13 ml) solution and ES+; m/z): 602 (100%); 600 (92%) ([NaEu(QC3A)]+). Elemental
stirred at ≈80 °C for 12 h. After neutralization with NaOH, anal. calc. for C22H24EuN3O6·(H2O)2 (MW 614.4): C, 43.00; H,
extraction with DCM was performed and the resulting aqueous 4.59; N, 6.84; O, 20.83 found: C, 42.97; H, 4.54; N, 6.74; O, 20.76.
solution was evaporated under reduced pressure. The solid
1H-NMR spectroscopy
was washed with ethanol for 1 h at 80 °C. Upon cooling, the
suspension was filtered to remove all the insoluble inorganic Nuclear magnetic resonance (NMR) experiments were per-
salts and the resulting solution was evaporated under reduced formed at 298.15 K using a 600 MHz Bruker Avance III spectro-
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meter equipped with a triple resonance TCI cryogenic probe. orange as an indicator.32 Free acid concentrations in lantha-
Spectra were usually recorded in CDCl3 and, unless otherwise nide solutions were checked by Gran’s method.29 Formation
noted, chemical shifts are expressed as ppm and referenced to constants were calculated by a simultaneous fit of the absor-
the internal standard tetramethylsilane (TMS). One dimen- bance values at several wavelengths using HypSpec.30
sional NMR spectra were recorded with 8 or 16 scans and a
spectral width of 12 019 Hz. All spectra were manually phased
and baseline corrected using TOPSPIN 3.2 (Bruker, Karlsruhe,
Germany). Chemical shift, multiplicity (s, singlet; d, doublet;
t, triplet; m, multiplet; b, broad), coupling constants and
integration area are reported.
ESI-MS
Electrospray ionization mass spectra (ESI-MS) were recorded
with a Finnigan LXQ Linear Ion Trap (Thermo Scientific, San
Jose, CA, USA) operating in positive ion mode. The data acqui-
sition was under the control of Xcalibur software (Thermo
Scientific). A MeOH solution of the sample was properly
diluted and infused into the ion source at a flow rate of 10 μL
min−1 with the aid of a syringe pump. The typical source con-
ditions were a transfer line capillary at 275 °C; ion spray
voltage at 4.70 kV; sheath, auxiliary and sweep gas (N2) flow
rates at 10, 5 and 0 arbitrary units, respectively. Helium was
used as the collision damping gas in the ion trap set at a
pressure of 1 mTorr.
Elemental analysis
Elemental analyses were carried out by using an EACE 1110
CHNOS analyzer.
Potentiometric titrations
The protonation constants of the ligands (bQcd (3), PyC3A (9)
and QC3A (13)) were determined by acid–base potentiometric
titrations. The titration cell was maintained at constant temp-
erature (298.15 0.1 K) using a circulatory bath. A computer-
controlled potentiometer (Amel Instruments, 338 pH meter)
DFT calculations
collected the electromotive force (emf) values measured by As the paramagnetic Eu(III) and Tb(III) complexes are rather
means of a combined glass electrode (Metrohm Unitrode difficult to model computationally, the analogues of the dia-
6.0259.100). Before each titration the electrode was calibrated magnetic Y(III) ion were studied. It has been shown that Y(III)
by an acid–base titration with standard HCl and NaOH solu- complexes may serve as suitable models for the Eu(III)
tions and the carbon dioxide contamination in solution was analogues,33–36 consistent with the fact that their ionic radii
checked by Gran’s method.29 Titrations were performed in differ from those of Eu(III) ions by about 0.05 Å [and less for
duplicate on solutions containing the ligand (typical concen- Tb(III)]. Geometry optimizations of the [Y(L)(H2O)n] complexes
tration around 0.9 mM for 3, 0.6 mM for 9 and 0.7 mM for 13) were carried out at the DFT level under vacuum using the
and an excess of standard HCl by adding standard NaOH solu- B3LYP exchange–correlation functional.37,38 The 6-31+G(d)
tion. The pH range was varied from an initial approximate basis set was employed for the ligand atoms, while the Y(III)
value of 2.3 to about pH 11.5. All the solutions were prepared ion was described by the quasi-relativistic small core Stuttgart–
with ultrapure water (>18 MΩ cm) from a Milli-Q system (ELGA Dresden pseudopotential and the relative basis set.39 This level
Purelab Option-Q) and the ionic strength (μ) was adjusted to of theory was previously demonstrated to provide correct geo-
0.1 M by using appropriate amounts of NaCl (Sigma-Aldrich). metries and thermochemical properties, also maintaining the
Among 50–70 points were collected in each titration and pro- calculation feasible with similar complex systems.23,33 All final
cessed with Hyperquad.30
geometries were checked to be minima by vibrational analysis.
Solvent effects were included by means of the PCM model.40
All calculations were carried out with Gaussian16.41
Spectrophotometric titrations
The formation constants of all the L–Ln(III) complexes (L = 3,
The complexes studied were the trans-O,O and trans-N,N
9, 13; Ln = Eu, Tb) were determined by UV-Vis spectrophoto- isomers of the Y(III) complexes ([Y(trans-O,O-bQcd)(H2O)5]+
metric acid–base titrations.31 A Varian Cary 50 instrument and [Y(trans-N,N-bQcd)(H2O)5]+), as the cis-O,O, cis-N,N isomer
equipped with a fibre optic (optical path of 10 mm) was used. was demonstrated to be much less stable in the case of bpcd.33
The wavelength range investigated was 240–300 nm for 9 and As previously done33 for the analogues with bpcd, five water
275–355 nm for 3 and 13 in the same pH range and μ as in the molecules were initially placed near the metal ion. During geo-
potentiometry. The titration cell was maintained at T = 298.15 metry optimization only two of them were retained in the first
0.1 K by means of a circulatory bath, and contained both coordination sphere. Also in the case of complexes with triace-
the ligand (ligand 3, 0.08 mM with Eu(III), 0.03 mM with tate ligands ([Y(PyC3A)(H2O)3] and [Y(QC3A)(H2O)3]) one water
Tb(III); ligand 9, 0.13 mM with Eu(III), 0.15 mM with Tb(III); molecule was always expelled from the starting structure to
ligand 13, 0.09 mM with both, Eu(III) and Tb(III)) and the Ln(III) provide a final complex with only two inner sphere water mole-
(1 : 1 L : Ln(III) ratio, with a slight metal excess). The NaOH and cules. Since the final number of coordinated water molecules
HCl stock solutions were the same as those used during the was 2 in all cases, the [Y(L)(H2O)2] complexes were considered
potentiometric titrations. The stock solutions of Eu(III) and Tb for structural comparisons. The calculations have been per-
(III) were prepared by dissolving their chloride hexahydrate formed on the two possible coordination geometries of the
salts (Sigma-Aldrich). The lanthanide content in the stock ligands (Fig. S1†) giving rise to [Y(trans-O,O-L)(H2O)2] and
solutions was determined by EDTA titration, using xylenol [Y(trans-N,O-L)(H2O)2] isomeric complexes.
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Luminescence and decay kinetics
following the Benesi–Hildebrand equation43 adapted to the
values of the asymmetry ratio (R) of the Eu(III) emission spectra:
Room temperature luminescence was measured with
a
R0
R ꢀ R0
R0
R0
Fluorolog 3 (Horiba-Jobin Yvon) spectrofluorometer, equipped
with a Xe lamp, a double excitation monochromator, a single
emission monochromator (mod. HR320) and a photomulti-
plier in photon counting mode for the detection of the
emitted signal. All the spectra were corrected for the spectral
distortions of the setup.
¼
þ
n
R
1 ꢀ R0 fKðR1 ꢀ R0Þ½HCO3ꢀꢁ g
where R0, R, and R∞ are the asymmetry ratios of Eu(III) in the
complexes considered in the absence of hydrogen carbonate, at
an intermediate hydrogen carbonate concentration and at a con-
centration of complete interaction, respectively. In the above
equation, K is the binding constant and n is the number of
hydrogen carbonate anions bound to the metal center and
[HCO3−] is the hydrogen carbonate concentration. The models
have been validated by the statistical tests present in the
MS-Excel cEST program here adapted to treat fluorescence data.44
In decay kinetics measurements, a xenon microsecond
flashlamp was used and the signal was recorded by means of a
multichannel scaling method. True decay times were obtained
using the convolution of the instrumental response function with
an exponential function and the least-squares-sum-based fitting
program (SpectraSolve software package). The total quantum
yields (ΦTot) have been obtained by secondary methods described
in the literature42 by measuring the visible emission spectrum of
quinine bisulfate in 1 N H2SO4 solution, a fluorescence quantum
yield reference sample (Φ = 54.6%). ΦTot for the complexes has
Results and discussion
been calculated by the [(As·Fu·n2)/(Au·Fs·n0 )]·Φs equation; where:
2
Synthesis
the u subscript refers to unknown and s to the standard and
other symbols have the following meanings: Φ is quantum yield,
A is the absorbance at the excitation wavelength, F is the inte-
grated emission area across the band and n’s are respectively
indexes of refraction of the solvent containing the unknown (n)
and the standard (n0) at the sodium D line and the temperature
of the emission measurement (see ESI, Fig. S15–S20†).
The synthesis of the ligands and the relative Ln(III) complexes
discussed in this paper are presented in Schemes 1 and 2.
For the synthesis of C1-symmetric ligands 9 and 13, we
exploit the straightforward chemistry of the t-butyloxycarbonyl
(BOC) protective group. In this context, the derivative 5
(Scheme 2) can be obtained in good yield as previously
reported.45 All the ligands (9 and 13) and the relative Ln com-
plexes (14 and 15) have been obtained in good yield and with a
high degree of purity (see the Experimental section for details).
The chlorides of the cationic complexes Eu(bpcd) and
−
Luminescence sensing of HCO3
The binding interactions between hydrogen carbonate and the
Eu(III) complexes were studied using the double reciprocal plot Tb(bpcd) were synthesized as reported previously.33 The synthesis
Scheme 1 Synthetic protocol for the synthesis of H2bQcd (3) and Eu(bQcd)(CF3SO3) (4). (a) 3 eq. tert-Butyl bromoacetate, 3.2 eq. K2CO3, MeCN,
room temperature, 12 h; (b) 6 M aq. HCl, 80 °C, 12 h; (c) 1 eq. Eu(OTf)3, 2-propanol, room temperature, 12 h.
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Scheme 2 Synthetic protocol for the synthesis of the ligands H3PyC3A (9), H3QC3A (13), the Eu(III) complexes Eu(PyC3A) (14a), Eu(QC3A) (15) and
the Tb(III) complex Tb(PyC3A) (14b). (a) 1 eq. pyridine-2-carbaldehyde, absolute ethanol, room temperature, 12 h; 1.2 eq. NaBH4, MeOH, room temp-
erature, 12 h; (b) 1 eq. quinoline-2-carbaldehyde, absolute ethanol, room temperature, 12 h; 1.2 eq. NaBH4, MeOH, room temperature, 12 h (c)
trifluoroacetic acid : dichloromethane (1 : 3), room temperature, 12 h; (d) 3.5 eq. tert-butyl bromoacetate, 3.5 eq. N,N-diisopropylethylamine, MeCN,
room temperature, 12 h; (e) 6 M aq. HCl, 80 °C, 12 h; (f) 1 eq. Eu(OTf)3, 2-propanol : ethanol (8 : 2), room temperature, 12 h; (1 g) 1 eq. Eu(OTf)3,
2-propanol : ethanol (1 : 1), room temperature, 12 h; (2 g) 1 eq. TbCl3·6H2O, water, room temperature, 12 h.
of 1 (Scheme 1) has already been reported previously,24 as well chiral DACH backbone: bpcd,33 PyC3A (9)46 and CDTA46 (1,2-
as the synthesis of 5.45
cyclohexanediaminetetraacetic acid). The titration curves for
ligands 3, 9 and 13 are displayed in Fig. S2, S3 and S4† respect-
ively, together with the speciation plots calculated by using the
Protonation constants
The best fit of the potentiometric data was obtained for all protonation constants shown in Table 1.
three ligands (3, 9 and 13) when four protonated species were
The log K values reported in Table 1 indicate that two fairly
considered. The obtained log Kn values are reported in Table 1 strong acidic and two weakly acidic sites are present. In par-
along with the constants for similar ligands containing the ticular, the values for the first protonation constant of the
Table 1 Protonation constants (log Kn, Kn = [LHn]/([H]·[LHn−1]) of the ligands 3, 9 and 13 with their confidence intervals (T = 298.15 K and μ = 0.1 M
NaCl). Additional protonation data for similar ligands are also reported. Charges are omitted for clarity
bQcd (3)
PyC3A (9)
QC3A (13)
bpcda
PyC3Ab
CDTAb
log K1
log K2
log K3
log K4
9.37 0.03
5.85 0.07
3.46 0.10
1.79 0.31
10.26 0.02
6.33 0.07
3.67 0.11
2.01 0.14
10.53 0.03
6.29 0.09
3.60 0.16
2.81 0.16
9.72 0.02
5.87 0.07
2.94 0.12
2.22 0.17
10.16 0.02
6.39 0.04
3.13 0.03
—
9.43 0.02
6.01 0.02
3.68 0.02
2.51 0.05
a
Ref. 33. b Ref. 46, μ = 0.15 M NaCl.
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Fig. 2 Species distribution of ligand 3 (L) along with the molar absor-
bance values at λ = 318 nm obtained by acid–base spectrophotometric
titration (T = 298.15 K, μ = 0.1 M NaCl). The speciation was calculated by
using the fitted protonation constants (Table 1) and the concentration of
3 ([L] = 0.09 mM dm−3). Charges are omitted for clarity.
ligands 3, 9 and 13 (Table 1) are in agreement with those
reported for tertiary amines (log K ∼ 6.9–10.7, depending on
the substituents).47 This suggests that the first protonation
constant can be assigned to an aliphatic amino group, as pre-
viously reported for bpcd33 and CDTA.48
Spectrophotometric acid–base titrations were performed in
order to study the species distribution of the ligand as a func-
tion of the pH. The molar absorbance (ελ) variations are
reported in Fig. 2, for ligand 3.
Similar plots are reported for ligands 9 and 13 in Fig. S5
and S6.† For ligand 3 (Fig. 2), ελ is nearly constant in the range
of 11–8.5 and then increases below pH ∼ 8.5 with the for-
mation of the bi- and tri-protonated species (log K2 = 5.85,
log K3 = 3.46). This change is related to the protonation of the
quinoline moieties, and is compatible with the protonation
constant of quinoline (log K = 4.97).49 The ελ values of 9 and 13
increase below pH ∼ 8 together with the formation of LH2
species, presumably related to the protonation of the pyridine
and quinoline moieties. The associated protonation values
(log K2 = 6.33 for 9, log K2 = 6.29 for 13) are in line with the pro-
tonation constants of 2-methylpyridine (picoline) and quino-
line (log K = 6.06 for picoline, log K = 4.97 for quinoline).49,50
The remaining protonation constants (log K4 for 3, log K3 and
log K4 for 9 and 13) could be ascribed to acetate moieties.51
Fig. 3 Species distribution of the complexes for the ligands (a)
3
(0.08 mM), (b) 9 (0.13 mM) and (c) 13 (0.09 mM) with Eu(III) (ratio 1 : 1
M : L, with a little excess of metal), along with the molar absorbance
values at λ = 318 nm (for the ligands 3 and 13) and λ = 265 nm (for
ligand 9) obtained by acid–base spectrophotometric titration at T =
298.15 K and μ = 0.1 M. Charges and negligible species (below 5%) are
omitted for clarity.
Ln(III) complex formation
The formation constants of the Eu(III) and Tb(III) complexes
with ligands 3, 9 and 13 were determined by acid–base spectro- function of pH. The same plots for the Tb(III) complexes are
photometric titration. In Fig. S7† the absorbance changes very similar to their Eu(III) analogues and are reported in
upon the addition of a base to equimolar solutions of Eu(III) Fig. S9.† In all plots, the formation of the complex is
and ligands 9 and 13 are shown. The spectra for the complexes accompanied by a steep decrease of ελ.
containing the same chromophore are very similar (Fig. S8†).
The best fit of the spectrophotometric data has been
In Fig. 3, the speciation diagrams for each studied Eu(III) obtained when only the ML species was considered and the
complex along with the ελ changes for quinoline- (λ = 318 nm) formation constants obtained for Eu(III) and Tb(III) are reported
and pyridine- (λ = 260 nm) based ligands are reported as a in Table 2 along with those available for similar ligands for
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Table 2 Formation constant (log β) complexes of the ligands 3, 9 and 13 with Eu(III) and Tb(III) at T = 298.15 K and μ = 0.1 M NaCl. Other similar
complexes have been added for comparison. Charges are omitted for clarity
Complex
bQcd (3)
PyC3A (9)
QC3A (13)
bpcda
bpedb
PEDTAc
CDTAd
Eu(III)L
Eu(III)L(OH)
Tb(III)L
Tb(III)L(OH)
Gd(III)L
Gd(III)L(OH)
9.97 0.08
—
9.80 0.13
—
—
—
15.682 0.009
—
15.70 0.02
—
—
—
12.55 0.16
—
12.08 0.28
—
—
—
11.19 0.32
2.18 0.57
11.36 0.15
2.04 0.33
—
—
—
—
—
12.37
2.1
—
—
—
—
15.56
—
19.6
—
20.0
—
19.6
—
—
a
Ref. 33. b Ref. 52, μ = 0.16 M NaCl. c Ref. 53. d Ref. 54.
comparison. According to this model, at pH = 7.4 the ML cations (i.e. DO3A derivatives with log β values in the 18–21
species is largely predominant in all cases (>99%).
range).56
Molecular models obtained by DFT calculations show that
As expected on the basis of the strong oxophilicity of Ln(III)
ions,55 the stability constants for the triacetate ligands [PyC3A Y(III) is 8-fold coordinated in all cases and additional water
(9) and QC3A (13)] are higher than their diacetate analogues molecules were expelled in the second-sphere as can be seen
[bpcd and bQcd (3) respectively]. Besides, the stability con- from the minimum energy structures in Fig. S10.† On this
stants of the Ln(III) complexes with the quinoline-substituted basis, further geometry optimizations were performed on the
ligands (3 and 13) are lower than for their pyridine analogues [Y(L)(H2O)2] complexes in the presence of PCM water. The
(bpcd and 9, respectively). This result could be due to a weaker increase of steric crowding when passing from pyridine- to the
interaction of the quinoline moieties with respect to the pyri- quinoline-substituted ligands can be clearly seen in Fig. 4.
dine ones and also to the increased steric hindrance. In the
From the obtained bond distances (Table 3) it emerges that
perspective of in vitro application experiments, the values of the substitution of pyridine by quinoline has nearly no effect
these formation constants appear promising, in particular for on the Y(III)–Oacetate bonds (average variation, ΔPy → Q ∼
triacetate-based ligands (9 and 13) whose stability is close to −0.001 and +0.005 Å for the di- and tri-acids, respectively),
that of macrocyclic ligands possessing similar coordination and also the Y(III)–Namine distances are marginally affected
ability and already employed in molecular imaging appli- (ΔPy → Q ∼ −0.019 and −0.006 Å). It can be also noted that
Fig. 4 Minimum energy structures of (a) [Y(trans-O,O-bpcd)(H2O)2]+; (b) [Y(trans-N,N-bpcd)(H2O)2]+; (c) [Y(trans-O,O-bQcd)(H2O)2]+; (d) [Y(trans-N,
N-bQcd)(H2O)2]+; (e) [Y(trans-O,O-PyC3A)(H2O)2]+; (f) [Y(trans-N,O-PyC3A)(H2O)2]+; (g) [Y(trans-O,O-QC3A)(H2O)2]+; (h) [Y(trans-N,O-QC3A)
(H2O)2]+.
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Table 3 Selected bond distances (Å) of the complexes in Fig. 4
Complex
Y–Oacetate
Y–Namine
Y–Nheterocycle
Y–Owater
[Y(trans-O,O bpcd)(H2O)2]+
[Y(trans-N,N bpcd)(H2O)2]+
[Y(trans-O,O bQcd)(H2O)2]+
[Y(trans-N,N bQcd)(H2O)2]+
[Y(trans-O,O PyC3A)(H2O)2]
[Y(trans-N,O PyC3A)(H2O)2]
[Y(trans-O,O QC3A)(H2O)2]
[Y(trans-N,O QC3A)(H2O)2]
2.262
2.292
2.268
2.284
2.286
2.300
2.286
2.290
2.550
2.610
2.557
2.567
2.568
2.595
2.574
2.576
2.525
2.503
2.661
2.594
2.550
2.546
2.654
2.642
2.448
2.492
2.464
2.482
2.474
2.539
2.458
2.478
Y(III)–Owater bonds are slightly longer in the pyridine triacid
isomers as it could be expected on the basis of the decreased
charge on the metal ion, while in the quinoline complexes
they are only slightly affected. However, the most remarkable
finding is that the average Y(III)–Nheterocycle bond distance
increases significantly (ΔPy → Q ∼ +0.11 Å), indicating the
weaker interaction of the quinoline with respect to pyridine
ligands with the metal ion; this possibly contributes to the
drop of stability of the quinoline complexes with respect to the
pyridine analogues (on average ∼1.4 and 3.4 log units for the
di and tri-acetate ligands). However, it is expected that quino-
line also has a notable impact on the solvation properties of
the complex which often have a strong influence on the
stability.
Luminescence
Fig. 6 Luminescence excitation spectra (left) and emission spectra
(right) of Eu(III) complex 14a and Eu(bpcd)Cl and Tb(III) complex 14b in
water solution (10−4 M) at 298 K. *Data from ref. 33.
Excitation spectra of the complexes 4, 14a, 15 and Eu(bpcd)Cl
dissolved in water upon monitoring the 5D0 → 7F2 transition of
Eu(III) (λem = 612–615 nm) are shown in Fig. 5 and 6 (left). In
the case of Tb(III) complex 14b, the excitation spectrum has
been recorded monitoring the 5D4
→
7F5 transition of Tb(III)
capable of sensitizing both Eu(III) and Tb(III) luminescence. On
the other hand, the quinoline ring effectively sensitizes only
the Eu(III) ion.
(λem = 545 nm, Fig. 6). As all the spectra are superimposable
with the corresponding absorption ones, a ligand to metal
energy transfer mechanism works in all the complexes under
investigation. As already observed33 the pyridine ring is
As far as the luminescence emission spectra are concerned
(Fig. 6 and 7, right), the typical Eu(III) or Tb(III) luminescence
originating from f–f transitions is clearly detected for all the
complexes. Upon excitation of the pyridine ring (λexc = 265 nm)
complexes 14a and Eu(bpcd)Cl showed a visual red lumine-
scence while complex 14b showed a green one. Upon excitation
of the quinoline ring (λexc = 319 nm) a red luminescence is
detected for complexes 4 and 15. In all the Eu(III) emission
5
7
spectra, the hypersensitive D0 → F2 transition dominates the
5
7
spectrum and one strong D0 → F0 band is also detected (in
particular in the case of quinoline-based complexes). All this is
compatible with the presence of emitting species where the
point symmetry of Eu(III) deviates from the inversion symmetry
and is characterized by an axial character.57 The Cn, Cnv or Cs
are the only possible point symmetries in the presence of size-
5
7
able intensity of the D0 → F0 transition57 even though in our
case, the Cs symmetry can be ruled out due to the presence of
the chiral ligand.
5
5
The luminescence decay curves of the D0 and D4 excited
states of Eu(III) and Tb(III), respectively were recorded in
aqueous solution for all the complexes under investigation; in
Fig. 5 Luminescence excitation spectra (left) and emission spectra
(right) of Eu(III) complexes 4 and 15 in water solution (10−4 M) at 298 K.
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one 6-fold coordinating ligand molecule and a different
number of water molecules (2 or 3) in the inner coordination
sphere of the metal ion.33 In addition, it has to be reminded
that the hydration number (q), calculated by the Horrocks
equation, is also slightly sensitive to the presence of water
molecules in the outer coordination sphere.58
The intrinsic quantum yield of the lanthanide ion (ΦLn),
defined by a number of emitted/absorbed photons, when
lanthanide ions are directly excited, is around 10% and 16%
for the Eu(III) and Tb(III) complexes, respectively (Table 4). The
higher values of the intrinsic quantum yield for the Tb(III)-
based complexes are due to the energy gap between the emit-
ting level and the lower lying ones, that is bigger in the case of
Tb(III) so as to limit the multiphonon relaxation process. On
the other hand, to estimate ηsens, we need to know the total
quantum yield (ΦTot), that is defined by the number of
photons emitted by the lanthanide ion/number of photons
Fig. 7 Eu(III) luminescence emission spectra of the complex 14a
(limited to 570–640 nm range) upon addition of hydrogen carbonate
ions. The concentration of the anion is reported.
absorbed by the ligand. Since, ΦTot = ηsens·ΦLn, then ηsens
=
ΦTot/ΦLn. The values of ΦTot for all the complexes have been
determined by using a reference standard of known quantum
yield (quinine bisulfate; Φ = 54.6%; see the Experimental
section for details). The obtained ηsens is in the 60–70% range
for all Eu(III) and Tb(III) complexes containing the pyridine
chromophore, whilst the Eu(III) complexes containing the qui-
noline fragment show a significantly lower sensitization
efficiency (in particular for Eu(bQcd)OTf, ηsens = 29%). This
seems to be related to the longer Y–Nheterocycle bond distances
found by DFT calculations, in the case of quinoline-based
complexes. In this context, it is useful to remember that the
probability of the energy transfer from an antenna ligand (S =
sensitizer) to a metal ion (A = acceptor) is strongly dependent
on the S–A distance, for both the most common energy trans-
fer processes taking place in lanthanide-based complexes
(dipole–dipole and exchange mechanisms).62 In particular, the
longer the distance, the lower is the energy transfer probability
and the sensitization efficiency. The seemingly low total
quantum yields (ΦTot in the 3–11% range) must be reassessed
in light of the following statements: (i) the quantum yield of
many lanthanide and d-block compounds used for cellular
imaging is in the 4–10% range;63,64 (ii) the total quantum yield
Fig. S12† we report only a representative selection. All the
curves are well fitted by a single exponential function and the
observed lifetimes, in water and deuterium oxide, are reported
in Table 4, together with the values of the hydration number
(q), the radiative lifetime (τrad), the intrinsic (ΦLn), the total
(ΦTot) quantum yields and the efficiency of the sensitization of
the lanthanide luminescence by the ligand (ηsens). The
hydration number is the number of water molecules in close
proximity of the metal ion and can be calculated by means of
the Horrocks equation58–60 that is based on the values of τobs
in H2O and D2O.
It is worth noting that the number of water molecules in
the inner coordination sphere of the metal ion in each
complex is, in practice, the same (around 2.5). This result
seems to be in partial agreement with the DFT structures
reported in Fig. 4 where always two water molecules are
retained in the first coordination sphere of the metal ion.
Nevertheless, as already observed for the complexes Eu(bpcd)
Cl and Tb(bpcd)Cl, this is compatible with the presence of an
equilibrium in solution interconverting two species having
Table 4 Observed and radiative excited state lifetimes (ms) for Eu(III) and Tb(III) complexes along with the number of water molecules (q) obtained
from data fitting. Intrinsic (ΦLn), total (ΦTot) quantum yields and ηsens are also reported
τobs
Complex
H2O
D2O
τrad
q
ΦLn (%)
ΦTot (%)
ηsens (%)
Eu(bpcd)Cl
Eu(bQcd)Cl
Eu(PyC3A)
Eu(QC3A)
Tb(bpcd)Cl
Tb(PyC3A)
0.30(1)
0.29(1)
0.33(1)
0.33(1)
0.94(1)
1.16(1)
1.70(1)
1.68(1)
3.56(1)
2.15(1)
2.15(1)
3.53(1)
3.00a
3.22a
3.66a
3.34a
5.98b
6.86b
2.7(1)
2.8(1)
2.7(1)
2.5(1)
2.6(5)
2.4(5)
10.0c
9.0c
6.1
2.6
5.67
4.0
10.0
11.2
61
29
63
40
64
66
9.0c
9.9c
15.7d
16.9d
a Estimated from the analysis of the Eu(III) emission spectra by using the formula reported by Werts et al.61 b Calculated by τrad = τobs/ΦLn; τobs
and ΦLn have been determined in H2O. c Estimated in aqueous solution thanks to the formula τobs/τrad
.
d Determined by using the reference
standard.
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of our complexes is expected to grow upon interaction of the the titration with HCO3−, the geometry of the Eu(III) environ-
complex with a target analyte thanks to the concomitant dis- ment is undergoing a change in symmetry. In fact, the values
placement of water molecules from the metal ion. For these of the asymmetry ratio:
reasons, we believe that the class of complexes under investi-
gation can be considered a promising family of optical probes
for sensing application.
5
7
Ið D0 ! F2Þ
R ¼
5
7
Ið D0 ! F1Þ
−
indicative of the degree of asymmetry of the coordination poly-
hedron around the Eu(III) ion, increase upon addition of the
anion.
Sensing of HCO3
As can be seen from the inspection of Fig. 7, the intensity of
5
7
5
7
the D0 → F0 and D0 → F2 Eu(III) transitions is significantly
affected by the addition of the hydrogen carbonate ion to
complex 14a (chosen as a representative example). As it is
reasonable to assume that the HCO3− anion is capable of coor-
dinating the Eu(III) ion, on displacing the water molecules
from the inner coordination sphere, we can claim that the
interaction between Eu(III) and the target anion produces an
increase in the intensity of 5D0 → 7F2 transition and a decrease
The value of R during the titration with hydrogen carbonate
also increases for all the Eu(III) complexes under investigation
(Fig. 8).
In all cases, a logarithmic-like trend is observed, and an
asymptote is reached after the addition of 10 mM of anion for
the Eu(III) complex with a bpcd ligand (Fig. 8). On the other
hand, the asymptotic value is reached only after the addition
of hydrogen carbonate at 15–20 mM, in the case of all the
other complexes [Eu(bQcd)OTf, Eu(PyC3A) and Eu(QC3A)]. The
5
7
in the intensity of the D0 → F0 one. This means that during
−
sensitivity of the optical response to the HCO3 concentration
can be qualitatively evaluated by analyzing the slope of the
graph in the range of biological interest where the hydrogen
carbonate concentration is related to serious metabolic acido-
sis (0–10 mM). As can be seen in Fig. 8, Eu(bpcd)Cl and
Eu(QC3A) (15) complexes show the best sensitivity. The
binding interactions between hydrogen carbonate and the
Eu(III) complexes were studied using the Benesi–Hildebrand
equation adapted to the values of the asymmetry ratio, as
described in the Experimental section. Since there is linearity
− 2−
in the plot of R0/(R − R0) vs. [HCO3
]
for Eu(bpcd)Cl and Eu
(bQcd)OTf (Fig. 9 and S13†) and in the plot of R0/(R − R0) vs.
− 1−
[HCO3
]
for Eu(PyC3A) and Eu(QC3A) (Fig. 10), the stoichio-
metry of the hydrogen carbonate adducts is 1 : 1 for Eu(PyC3A)
and Eu(QC3A) complexes and 1 : 2 for Eu(bpcd)Cl and
Eu(bQcd)OTf ones.
Since the affinity of the anion for the Ln(III) centre is mainly
determined by coulombic attraction it is not surprising that
the cationic complexes Eu(bpcd)Cl and Eu(bQcd)OTf can coor-
dinate the hydrogen carbonate anion with high affinity con-
Fig. 8 Asymmetry ratio (R) for the Eu(III) complexes vs. [HCO3−] con-
centration plots. The employed ligands are reported in each plot (refer-
ence labels in Fig. 1).
− −2
Fig. 9 Benesi–Hildebrand plot vs. [HCO3
]
(M−2) for (a) [Eu(bpcd)]+ and (b) [Eu(bQcd)]+ complexes. R0 is the asymmetry ratio of the starting
complex; R is the asymmetry ratio after each addition of the analyte. R and R0 have been calculated from the relative Eu(III) luminescence emission
spectrum.
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− −1
Fig. 10 Benesi–Hildebrand plot vs. [HCO3
]
(M−1) for (a) Eu(PyC3A) and (b) Eu(QC3A) complexes. R0 is the asymmetry ratio of the starting
complex; R is the asymmetry ratio after each addition of the analyte. R and R0 have been calculated from the relative Eu(III) luminescence emission
spectrum.
Table 5 Apparent equilibrium constants (log K) for the formation of the
adducts with hydrogen carbonate (HCO3−), [complex] + n·hydrogen car-
bonate ⇄ [complex(hydrogen carbonate)n] (T = 298 K, pH 7.40 ( 0.05),
I = 0.1 M NaCl, 40 μM complex), determined through fluorimetric titra-
tion. Charges are omitted for clarity
Complex
n
log K
Eu(bpcd)Cl/Tb(bpcd)Cl
Eu(bQcd)(CF3SO3)
Eu(PyC3A)
2
2
1
1
5.76(8)/5.94(8)
4.62(8)
2.06(8)
Eu(QC3A)
3.11(8)
Fig. 11 Minimum energy structures of the [Y(trans-O,O-bpcd)(HCO3)2]−
complexes obtained in PCM water with (a) bis-monodentate and (b) bis-
bidentate hydrogen carbonate coordination modes.
stants (calculated from the ratio of intercept/slope of the
Benesi–Hildebrand plot, Table 5). To the best of our knowl-
edge, a value of log K higher than 4, in the case of the hydro-
gen carbonate ion, is unprecedented in the literature and this 1 : 2 species. Furthermore, it is worth underlining that the
is probably related to the unusual number of target anions presence of the quinoline ring affects the stability of the
bound to the metal center. The Eu(III) in these complexes can adduct with hydrogen carbonate. In the case of cationic com-
bind up to 2 hydrogen carbonate units, likely due, as discussed plexes, the adduct with quinoline is less stable compared to
in the Introduction, to the lower number of donating atoms the one with pyridine. In contrast, an opposite trend is
(6-fold coordination) than in the case of ligands commonly observed for the neutral complexes. The reasons of such be-
employed for Ln(III)-based luminescence anion sensing (NOTA havior in the case of the diacid ligand could be found in the
and DOTA-like possessing 7-fold coordination). The possible high steric hindrance of the heteroaromatic ring which, at
structures of the 1 : 2 hydrogen carbonate adducts to [Y(trans- least for the trans-O,O-bQcd isomer (Fig. 4c), presents two
O,O-bpcd)(H2O)2]+ obtained by DFT calculations (Fig. 11) show hydrogen atoms pointing towards the inner coordination
two possible coordination modes. However, the bis-monoden- sphere, thus likely to hinder the coordination of hydrogen car-
tate hydrogen carbonate seems to be the only possible isomer bonate and maybe giving rise to an affinity constant one order
being 10.3 kcal mol−1 more stable than the bis-bidentate one of magnitude lower than for the pyridine-based analog. Here,
(also the latter presents an imaginary vibrational mode corres- we demonstrate how, thanks to a modulation of the steric hin-
ponding to the opening of two Y–O bonds). The optimization drance at the metal ion using the different ligands shown in
of the 1 : 2 adduct with both hydrogen carbonate coordination Fig. 1, it is possible to tune the affinity (and the selectivity) of
−
modes (one bi- and one mono-dentate) led always to a bis- the complexes towards HCO3
monodentate structure.
.
As far as the affinity of the analogous Tb(III) complexes
Due to the neutral charge of Eu(PyC3A) and Eu(QC3A) com- towards hydrogen carbonate is concerned, we expect a behav-
plexes, it is not surprising to find in their adducts with hydro- ior similar to the one observed for Eu(III) derivatives, since
gen carbonate lower binding constants and a 1 : 1 stoichio- Eu(III) and Tb(III) complexes are often isostructural due to the
metry. It is also reasonable to assume that the negative charge similarity of their ionic radii.55 As expected, the calculated
of the 1 : 1 adduct hampers the formation of the bis-anionic affinity constant for the Tb(bpcd)Cl complex, chosen as a
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representative example, is similar to the one of Eu(bpcd)Cl
(Table 5 and Fig. S14†).
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