Filip
Koucký
,
Jan
Kotek
*,
Ivana
Císařová
,
Jana
Havlíčková
,
Vojtěch
Kubíček
and
Petr
Hermann
Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 42 Prague 2, Czech Republic. E-mail: modrej@natur.cuni.cz
First published on 16th June 2023
A new cyclam-based ligand bearing two methylene(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent transition metal ions [Co(II), Ni(II), Cu(II), Zn(II)] was studied. The ligand was found to be very selective for the Cu(II) ion according to the common Williams–Irving trend. Complexes with all the studied metal ions were structurally characterized. The Cu(II) ion forms two isomeric complexes; the pentacoordinated isomer pc-[Cu(L)] is the kinetic product and the octahedral trans-O,O′-[Cu(L)] isomer is the final (thermodynamic) product of the complexation reaction. Other studied metal ions form octahedral cis-O,O′-[M(L)] complexes. The complexes with paramagnetic metal ions showed a significant shortening of 19F NMR longitudinal relaxation times (T1) to the millisecond range [Ni(II) and Cu(II) complexes] or tens of milliseconds [Co(II) complex] at the temperature and magnetic field relevant for 19F magnetic resonance imaging (MRI). Such a short T1 results from a short distance between the paramagnetic metal ion and the fluorine atoms (∼6.1–6.4 Å). The complexes show high kinetic inertness towards acid-assisted dissociation; in particular, the trans-O,O′-[Cu(L)] complex was found to be extremely inert with a dissociation half-time of 2.8 h in 1 M HCl at 90 °C. Together with the short relaxation time, it potentially enables in vitro/in vivo utilization of the complexes as efficient contrast agents for 19F MRI.
A number of compounds have been tested as 19F NMR contrast agents. They were usually perfluorinated hydrocarbons and their derivatives (for simplicity, they are called perfluorocarbons, PFCs), and some of them have been already studied for a long time as potential blood substitutes.9,10 The list of compounds includes e.g. hexafluorobenzene,11 perfluorodecalin,12 tris(perfluoroalkyl)amines,13 perfluorinated crown ethers,14–18 fluorinated polymers,19etc., which are used in the form of nanoemulsions. However, these organic compounds show very long T1 relaxation times. Therefore, a long delay between excitation pulses is needed, which prolongs the total acquisition time. To shorten the time of imaging, complexes of fluorine-containing ligands with paramagnetic metal ions were introduced.20–22 They are usually complexes of lanthanide(III) ions [with a generally large magnetic momentum, especially for Dy(III) and Ho(III)] with ligands based on a cyclen (1,4,7,10-tetraazacyclododecane) skeleton (e.g. H4dota derivatives, Fig. 1),23,24 which ensures kinetic inertness of these contrast agents.25,26 More recently, transition metal ion complexes have been also found to effectively shorten T1 relaxation times.27–30 Here, especially complexes of cyclam-based ligands (cyclam = 1,4,8,11-tetraazacyclotetradecane, Fig. 1) were found to be promising.31–36 In general, the cyclam derivatives are not suitable for complexation of lanthanide ions due to an inappropriately large macrocyclic cavity, but they are well known for effective binding of heavier first-row transition metal ions. In particular, Cu(II) and Ni(II) ions are bound very selectively into thermodynamically stable and kinetically inert complexes.37–41 However, some Ni(II) complexes of 1,8-bis(2,2,2-trifluoroethyl)-cyclam derivatives (1,8-tfe2cyclams, Fig. 1) showed decreased stability and kinetic inertness, and have in general very short relaxation times (in the millisecond range) due to a very short distance between the paramagnetic centre and fluorine atoms, which prevents simple measurement and places non-trivial demands on the hardware used for imaging.32 In this respect, analogous Co(II) complexes with T1 ∼ 10–15 ms seem to be more promising.34 In addition, we designed a series of ligands with larger separation of the fluorine atoms from the paramagnetic metal ion centre [1,8-(tfe-NHR)2cyclams, Fig. 1].42 It was shown that complexation of Cu(II) to these structures shortens significantly fluorine relaxation times to an optimal range (order of tenths of milliseconds).42 Some time ago, we introduced (2,2,2-trifluoroethyl)phosphinic acid as a suitable pendant arm in the cyclen-based ligand H4dotptfe (Fig. 1) and studied its lanthanide(III) complexes.43 To extend our work in this field, we report on the results of our study of a new cyclam derivative with two (2,2,2-trifluoroethyl)phosphinic acid pendant moieties in the 1,8-positions (H2L, Fig. 1).
Thin-layer chromatography (TLC) was performed on silica-coated aluminium sheets, silica gel 60 F254 (Merck). Spots were visualized using UV light (254 and 366 nm), spraying with 0.5% ethanolic solution of ninhydrin, and dipping in 5% aq. solution of CuSO4, iodine vapour or in aq. solution of 1% KMnO4 and 2% Na2CO3.
NMR spectra were recorded on NMR spectrometers Varian VNMRS300 equipped with a pseudo-4-chanel probe (frequencies 299.9 MHz for 1H, 282.2 MHz for 19F and 121.4 MHz for 31P), Varian Inova 400 MHz (frequencies 400.0 MHz for 1H, 100.6 MHz for 13C, 376.3 MHz for 19F and 161.9 MHz for 31P) equipped with an ID-PFG probe for 19F relaxation experiments or with an ASW 4NUC probe, or Bruker Avance III 600 MHz (frequencies 600.2 MHz for 1H, 150.9 MHz for 13C and 564.7 MHz for 19F) equipped with a cryoprobe (1H, 13C, 15N) or with a BBO probe (19F). Representative NMR spectra of the prepared compounds are given in the ESI.† The spectra were acquired at 25 °C unless stated otherwise. Internal references for 1H and 13C NMR spectra were t-BuOH for D2O solutions and the CHD2OD residual peak for MeOH-d4 solutions, respectively. Aq. H3PO4 (3%) was used as the external reference for 31P NMR, and ca. 1% triflic acid for 19F NMR. These secondary references were referenced to 85% H3PO4 (0.0 ppm) and to Freon-11 (0.0 ppm) respectively. Chemical shifts are given in ppm and coupling constants at Hz. Chemical shifts of paramagnetic compounds were corrected for the bulk magnetic susceptibility effect: to the sample, a small amount of 2,2,2-trifluoroethanol was added, and the chemical shift was measured using an insert cuvette containing the secondary reference. The same insert cuvette was used to measure the chemical shift of 2,2,2-trifluoroethanol in a pure solvent, and the difference between the signals of trifluoroethanol was used for chemical shift correction of the paramagnetic compound. The T1 relaxation times of the 19F NMR signal were measured with the inversion recovery sequence. The T2 relaxation times of diamagnetic compounds were measured with the CPMG sequence on Varian Inova 400 MHz and Bruker III 600 MHz; the measurement is not accessible on VNMRS300 as the probe used does not provide accurate 180° pulses for 19F nuclei. The relaxation times were calculated for all paramagnetic complexes from half-widths of the NMR signals.
Mass spectra were recorded on a Waters ACQUITY QDa, which is a part of the Waters Arc HPLC system. Data were processed using Empower 3 software. Samples were dissolved in water, MeOH or MeCN. The HPLC was run on the same device using the Cortecs C18 2.7 μm, 4.6 × 50 mm column and H2O:
MeCN 100 to 0% gradient [0.1% trifluoroacetic acid (tfa) used as a modifier].
The UV-Vis spectra were recorded on a spectrometer Specord 50 Plus (Analytic Jena) in a quartz–glass cell with an optical path of 1 cm in the range of 350–1100 nm.
The volatiles were evaporated on a rotary evaporator at a bath temperature of 50 °C. The remaining material was poured onto a column of a strong cation exchange resin in a H+-cycle (Dowex 50, 500 ml) and the mixture of acids was eluted with water (DIPEA was retained on the column). Acid fractions were concentrated on a rotary evaporator at 40 °C. The 1H NMR spectrum confirmed the absence of DIPEA in the eluted material. After this procedure, ethyl ester of 2 present in the initial mixture was completely hydrolysed.
A solution of Pb(OAc)2 in 20% acetic acid (1 M, 70 ml) was added into the evaporated eluate obtained above and diluted with water (50 ml). The mixture was stirred at room temperature for 3 h and the yellow precipitate of PbI2 was removed by filtration on a Büchner funnel through several layers of filtration paper. Excess Pb(II) in the filtrate was removed by bubbling hydrogen sulphide through the solution and the PbS precipitate was filtered off using a Büchner funnel with a paper mesh. Volatiles from the filtrate were removed at 50 °C using a rotary evaporator.
The product was purified on a silica column (300 ml) using conc. aq. NH3:
EtOH 1
:
20 as a mobile phase [Rf(product) 0.65, Rf(H3PO3) 0.35]. Fractions containing the pure product were combined and evaporated giving the ammonium salt of (2,2,2-trifluoroethyl)phosphinic acid as a white solid. Free acid was obtained by passing a solution of the ammonium salt through a column of a strong cation exchange resin (Dowex 50, H+-form, 100 ml, elution with water) and evaporation of the eluate at 40 °C. Yield 9.0 g (57%) as a clear colourless oil.
NMR (ammonium salt, D2O, pD 4.6). 1H: 7.15 (d; 1H; HP; 1JHP 547), 2.63 (m; 2H; CH2). 13C{1H}: 37.5 (dq; CH2; 2JCF 27.3, 1JCP 81.3), 125.8 (qd; CF3; 1JCF 275; 2JCP 3.1). 19F: −57.7 (pseudo-q; 3JFH ≈ 3JFP ≈ 12.0). 31P{1H}: 13.3 (q, 3JPF 12.0). 31P: 13.3 (dm, 1JPH 547). MS-ESI, (+): 149.0 [M + H]+; (−): 146.7 [M − H]−. TLC (conc. aq. NH3:
EtOH 1
:
20): Rf 0.65 (ninhydrin, yellow spot; KMnO4/Na2CO3, yellow spot).
EA (H23·6CF3CO2H·2H2O): found (calc. for C42H54F24N4O18P2, Mr 1420.81) C: 35.68 (35.51), H: 3.60 (3.83), N: 3.73 (3.94), F: 31.28 (32.09), P: 4.13 (4.36). NMR (H23·6H2O, MeOH-d4, atom numbering scheme is given in the ESI†). 1H: 2.11–2.30 (4H, m, H6); 2.33–2.40 (2H, m, H2); 2.43–2.58 (6H, m, H9 and H8); 2.60–2.67 (2H, m, H8); 2.78–2.86 (4H, m, H5 and H7); 2.91–3.01 (4H, m, H3 and H7); 3.26–3.34 (1H, m, H3); 3.34–3.41 (2H, m, H2); 3.68–3.74 (2H, m, H5); 4.21–4.27 (2H, m, H11); 4.39–4.46 (2H, m, H11); 7.47–7.53 (6H, m, H14 and H15); 7.56–7.61 (4H, m, H13). 13C{1H}: 24.56 (s, C6); 37.32 (dq, C9, 2JCP 79.6, 2JCF 28.2); 49.9 (s, C2); 50.3 (s, C5); 52.0 (s, C3); 54.9 (d, C8, 2JCP 119); 58.5 (s, C7); 58.8 (s, C11); 127.8 (q, C10, 1JCF 275.1 Hz); 130.8 (s, C12); 131.1 (s, C14); 131.9 (s, C15); 134.1 (s, C13). 19F: −58.06 (dt; 3JFH 12.3, 3JFP 6.8). 31P{1H}: 23.4 (q, 3JPF 6.9). 31P: 23.5 (m). MS-ESI, (+): 701.4 [M + H]+; (−): 699.4 [M − H]−. TLC (conc. aq. NH3:
EtOH 1
:
10): Rf 0.80 (CuSO4, green spot).
EA [(H6L)Cl4·4H2O]: found (calc. for C16H44Cl4F6N4O8P2Mr 738.29) C: 27.07 (26.03), H: 5.30 (6.01), N: 7.94 (7.59), F: 15.63 (15.44), P: 8.16 (8.39), Cl: 19.36 (19.21). NMR [(H6L)Cl4·4H2O, D2O, pD 9.0 (NaOD), atom numbering scheme is given in the ESI†]. 1H: 1.97 (4H, bs, H6); 2.72 (4H, pseudo-p, 3JHF ≈ 3JHP ≈ 12.4, H9); 2.85 (4H, bs, H2 and H8); 2.92 (8H, bs, H2 and H7); 3.12 (4H, bs, H3); 3.21 (4H, t, 3JHH 5.9, H5). 13C{1H}: 24.1 (s, C6); 35.1 (dq, C9, 1JCP 79.5, 2JCF 28.6); 45.9 (s, C3); 48.2 (s, C5); 54.5 (d, C8, 1JCP 117.3); 55.4 (d, C2, 3JCP 6.6); 58.8 (d, C7, 3JCP 5.5); 125.7 (qd, C10, 1JCF 274.9, 2JCP 3.2). 19F: −57.34 (dt; 3JFH 12.0, 3JFP 7.2). 31P{1H}: 28.5 (q, 3JPF 7.3). 31P: 28.5 (m). MS-ESI, (+): 521.2 [M + H]+, 1041.5 [2M + H]+. TLC (conc. aq. NH3:
EtOH 1
:
5): Rf 0.80 (CuSO4, violet spot).
Attempts to prepare complexes of H23 with Co(II), Ni(II) and Zn(II) by mixing H23 with MCl2 in aq. MeOH solutions and addition of aq. ammonia as a base led to the formation of precipitates insoluble in all common solvents (H2O, MeOH, EtOH, DMSO, DMF, CHCl3).
Solutions of complexes for 19F NMR characterization were prepared directly in the NMR tube by mixing 150 μl of 18.4 mM solution of (H6L)Cl4·4H2O used for potentiometry, HEPES buffer (300 μl, 0.5 M, pH 7.4) and an appropriate volume of the solution of the metal salt (ca. 50 mM). The Zn(II) complex was prepared by mixing the ligand and a slight excess (1.2 equiv.) of ZnCl2 to ensure the absence of free H2L as, due to diamagnetism of the sample, the signal of free H2L would be hardly distinguishable from the signal(s) of the complex isomers; it would complicate the interpretation of the NMR spectra. The Ni(II) and Co(II) complexes were prepared using a slightly sub-stoichiometric amount of Ni(NO3)2 or Co(NO3)2, respectively. In these cases, the signal of the diamagnetic H2L excess was used as an internal reference. For the Co(II) complex, the NMR tube was flushed with Ar and pH was increased to 8.0 with aq. NaOH to ensure the full complexation of Co(II) ions (according to the results of the potentiometric study, see below). The Co(II) complex showed one 19F NMR signal (−38.6 ppm, Fig. S1†) which remained unchanged with further standing (only some negligible oxidation to diamagnetic Co(III) was observed if the tube was opened to air; a very small diamagnetic signal appeared); further study revealed its cis-O,O′-[Co(L)] geometry (see below). However, solutions containing Ni(II) and Zn(II) complexes showed complicated spectra. Therefore, the samples were equilibrated for several days at 80 °C. The measured 19F NMR spectra of the fully equilibrated solutions showed one major signal of the Ni(II) complex at −47.1 ppm (∼80%) besides two minor signals at −43.7 and −47.7 ppm with equal intensity (each ∼10%), as shown in Fig. S2.† Based on a further 19F NMR study, the cis-O,O′-[Ni(L)] geometry was suggested with R/S isomerism of the phosphorus atom (see below). In the case of the Zn(II)–H2L system, an isomeric mixture of three complexes was observed (pseudo-quartets due to 19F–31P/1H couplings centred at −57.15 pm, ∼40%; −57.23 ppm, ∼55%; −57.30 ppm, ∼5%, Fig. S3†). In the case of the diamagnetic Zn(II)–H2L system, it was possible to acquire the 31P NMR spectra also, which were consistent with the 19F NMR data (three signals in 31P NMR spectra, 30.1 pm, ∼55%; 29.4 ppm, ∼5%; 28.7 ppm, ∼40%, Fig. S4†). The same 19F and 31P NMR spectra were observed for several independently prepared samples of the [Zn(L)] complex after the equilibration.
An alternative way was used to prepare complex solutions without additional salts and excess ligand: a solution of H2L (46.0 mM, 840 μl, ca. 20 mg of H2L) was mixed with 1.5 equiv. of CoCO3 (7 mg) or with freshly precipitated M(OH)2 excess [M = Ni, Zn prepared by the addition of aq. LiOH to aq. MCl2 (2.0 equiv.) and washing the precipitate with water by repeated centrifugation]. The mixtures were stirred in a closed vial at 80 °C for 5 d. After cooling, the excess of the solid phase was filtered off and the filtrate was concentrated. The measured 19F NMR spectra confirmed the absence of free H2L and showed the same signals of the complexes as found in the samples mentioned above, including the same ratio of the isomeric species.
The formation of the complexes was confirmed also by mass spectrometry. MS-ESI, (+): [Co(L)]: 578.2 [59CoL+ H]+; 577.2, [59CoL]+; [Ni(L)]: 577.1 [58NiL + H]+; [Zn(L)]: 583.2 [64ZnL + H]+.
Single crystals of cis-O,O′-[Co(L)]·LiCl·3H2O were prepared by acetone vapour diffusion into a solution of the complex prepared from a mixture of H2L and CoCl2 neutralized with LiOH.
Single crystals of cis-O,O′-[Ni(L)]·3.5H2O and cis-O,O′-[Zn(L)]·2H2O·0.5acetone were formed on acetone vapour diffusion into solutions of the corresponding complexes prepared from M(OH)2 as described above.
Alternatively, 46.0 mM solution of H2L (840 μl, ca. 20 mg of H2L) was mixed with freshly precipitated Cu(OH)2 prepared by addition of 2% aq. LiOH to aq. solution of CuCl2·2H2O (13 mg, 2.0 equiv.) and washing the precipitate with water by repeated centrifugation. The mixture was stirred in a closed vial at room temperature overnight. The excess of Cu(OH)2 was filtered off and the filtrate was concentrated. The TLC analysis showed exclusive formation of the pc-[Cu(L)] isomer. The measured 19F NMR spectra confirmed the absence of free H2L and presence of the signal belonging to the pc-[Cu(L)] complex as mentioned above. TLC (conc. aq. NH3:
EtOH 2
:
3): Rf 0.80 (blue spot, Fig. S7†). MS-ESI: (+): 581.9 [M + H]+, 603.9 [M + Na]+.
Single crystals of pc-[Cu(L)]·3H2O were formed on acetone vapour diffusion into a concentrated aqueous solution of the complex.
Alternatively, 46.0 mM solution of H2L (1.25 ml, ca. 30 mg of H2L) and CuCl2·2H2O (10 mg, 1 equiv.) was neutralized to pH 7.4 with LiOH and heated at 90 °C for 5 d. The volatiles were evaporated and the complex was purified by chromatography on silica using conc. aq. NH3:
EtOH 2
:
3 as a mobile phase. The violet-coloured fraction was evaporated to dryness. The measured 19F NMR spectra confirmed the absence of free ligand and presence of one signal of the trans-Cu(II)-complex. TLC (conc. aq. NH3
:
EtOH 2
:
3): Rf 0.95 (violet spot, Fig. S7†). MS-ESI: (+): 581.9 [M + H]+, 603.9 [M + Na]+.
Single crystals of trans-O,O′-[Cu(L)]·NH4(Cl0.54Br0.46) were formed on acetone vapour diffusion into concentrated chromatographic fractions containing the complex.
Single crystals of trans-O,O′-[Cu(L)]·(H3O)(ClO4)·H2O were crystallized by cooling of the saturated solution of the complex in boiling 1 M HClO4.
Data were analysed using the SAINT V8.34A–V8.40B software package (Bruker AXS Inc., 2015–2019). Data were corrected for absorption effects using the multi-scan method (SADABS).46 All structures were solved by the direct methods (SHELXT2014)47 and refined using full-matrix least-squares techniques (SHELXL2014).48 Details on structure refinement are given in the ESI.†
All the data for the structures reported here have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 2262037–2262048 (for an overview of experimental crystallographic data, see Table S1†).
The ligand stock solution was prepared by the dissolution of (H6L)Cl4·4H2O (1.3217 g) in a 100 ml volumetric flask. The solid (H6L)Cl4·4H2O is slightly unstable due to the loss of HCl and water and, thus, the exact ligand concentration was determined by 19F qNMR (18.4 mM) using standardized aq. solution of tfa. This value agrees well with the value calculated during the fitting of the protonation constants (difference < 1%). The overall protonation constants βn are concentration constants and are defined by βn = [HnL]/([H]n·[L]) (stepwise protonation constants are defined as logK1 = log
β1; log
Kn = log
βn − log
βn−1). The overall stability constants are defined by the general equation βhml = [MmHhLl]/([M]m·[H]h·[L]l). Here, the formation of only M
:
L = 1
:
1 complexes (m = l = 1) was suggested. The constants (with their standard deviations) were calculated with the OPIUM program.51 The protonation constants were determined using standard titrations in the pH range 1.6–12.1 with cL = 0.004 M and starting volume approx. 5 ml (pH means “analytical” pH, –log[H+]). Equilibrium was established slowly in the metal(II)-containing systems. Therefore, stability constants of the complexes were obtained by the “out-of-cell” method. Each solution corresponding to one titration point of a common titration was prepared under an Ar stream in tubes with ground joints (pH 1.6–6.5, three titrations with 15 points) from the ligand, metal ion and HCl/(NMe4)Cl stock solutions and water (starting volume ca. 1 ml, M
:
L molar ratio 0.95
:
1, cL = 0.004 M). Then, a known amount of (NMe4)OH standard solution was added under Ar. The tubes were firmly closed with stoppers and the solutions were left to equilibrate at room temperature. Afterwards, pH was measured with a freshly calibrated combined glass electrode in each tube. One set of tubes containing the Cu(II)–H2L system was equilibrated for three weeks and the others for four weeks. Systems with Co(II), Ni(II) and Zn(II) were equilibrated for six weeks (one set of each metal ion) and eight weeks (the remaining sets). Identical results were obtained in both time points for each metal ion system proving a reaching the thermodynamic equilibrium after the shorter time period used.
The key starting compound, 2,2,2-trifluoroethylphosphinic acid 2, was prepared by an Arbuzov-type reaction between 2,2,2-trifluoroethyl iodide and bis(trimethylsilyl)hypophosphite which was generated in situ from hypophosphorous acid and trimethylsilyl chloride in the presence of N,N-diisopropylethylamine (DIPEA) as a base. The silyl ester intermediate was hydrolysed with aqueous ethanol leading to the product 2 with conversion in the range of 60–80% (according to the intensity of the 31P NMR signal (14.5 ppm, 1JPH = 576 Hz) and phosphorous acid as a dominant by-product (1.8 ppm, 1JPH = 660 Hz). Despite an excess of the alkylation agent used, no bis(2,2,2-trifluoroethyl)phosphinic acid was formed during the reaction, probably due to the low nucleophilicity of the monosubstituted derivative and volatility of the starting alkylation agent (Ar flow was used to ensure an inert atmosphere).
DIPEA was removed on a strong cation exchange resin in the H+-form and the acid eluate containing predominantly product 2, phosphorous acid and hydroiodic acid was evaporated at <40 °C (in bath) to avoid oxidation/disproportionation of product 2. However, under such conditions, it was impossible to quantitatively remove HI. Any HI present in the crude product mixture forms elemental iodine on standing which oxidizes the compound 2 to 2,2,2-trifluoroethylphosphonic acid. HI was removed with an excess of lead(II) which was then precipitated by gaseous H2S. The separation of product 2 and phosphorous acid was accomplished by chromatography on silica using aq. NH3:
EtOH 1
:
20 as a mobile phase. After chromatography, the product was isolated in the form of a semi-solid ammonium salt. It was converted to free acid on a strong cation exchanger in the H+-form. Free acid 2 was isolated as a colourless oil in a moderate yield.
A Mannich-type reaction between 1,8-dibenzyl-cyclam 1, 2,2,2-trifluoroethylphosphinic acid 2 and paraformaldehyde was performed in a strong acid solution (water:
trifluoroacetic acid 1
:
1) at 60 °C. Aq. HCl usually used as a solvent for this type of reaction cannot be used here due to the insolubility of the starting amine 1 in the solvent. In less acidic media (acetic acid), the reaction did not proceed even at 80 °C but the oxidation of the P–H bond was observed instead. The product H23 is insoluble in the reaction medium and was separated by filtration as an adduct with trifluoroacetic acid. Re-crystallization of the product from water
:
trifluoroacetic acid (1
:
1) afforded single crystals of H23·6CF3CO2H·2H2O suitable for X-ray diffraction analysis (see the ESI†). Despite the presence of several strong acid molecules in the solid-state structure, the macrocycle is only double-protonated and the protons are located on amino groups bearing the benzyl groups. Trifluoroacetic acid was removed by the re-crystallization of H23·6CF3CO2H·2H2O from water and H23·6H2O was obtained. Slow cooling of the saturated hot aq. solution afforded crystals suitable for the X-ray diffraction study (see the ESI†).
Debenzylation of the intermediate H23 to H2L was performed in 90% v/v aq. acetic acid under a H2 atmosphere using Pd/C as a catalyst. After catalyst removal, ligand H2L was isolated by the crystallization of the concentrated reaction mixture as a zwitterionic adduct with acetic acid H2L·4AcOH. The procedure afforded single crystals of sufficient quality for the determination of the crystal structure. It revealed deprotonation of the phosphinate arms and protonation of the secondary amino groups, i.e. H2L is present in a zwitterionic form (Fig. 2).
The zwitterionic molecule of H2L possesses a centre of symmetry and adopts a “common” angular conformation similar to those found in the crystal structure of the cyclam itself and in its diprotonated forms.52,53 The phosphinate pendant arms are turned above/below the macrocyclic cavity and stabilize the molecular conformation by strong intramolecular hydrogen bonds [d(N4#⋯O11) = 2.71 Å, d(N4⋯O12) = 2.85 Å]. Both molecules of the co-crystallized acetic acid are protonated and are bound by very strong hydrogen bonds to the phosphinate oxygen atoms {d(O[AcOH]⋯O11/O12) = 2.58 Å, Fig. S21†}.
The ligand H2L can be easily converted into hydrochloride (H6L)Cl4·4H2O by the crystallization of H2L·4AcOH from aq. HCl (6 M). Further re-crystallization of this material from water afforded (H4L)Cl2·4H2O which was structurally characterized. In the presence of HCl, all macrocycle amino groups of the ligand molecule are protonated which leads to the conformation (3,4,3,4)-D52,53 of the cyclam ring. The nitrogen atoms bearing the phosphinate pendant arms form the corners of the (3,4,3,4)-D rectangle (Fig. 3). Such a conformation maximizes the separation of the positive charges but avoids the formation of intramolecular hydrogen bonds, and only a wide network of intermolecular contacts is formed.
Attempts to structurally characterize the ligand in its deprotonated form by the crystallization of H2L solution neutralised by LiOH to pH ca. 9 (a higher pH leads to a slow degradation of the ligand molecule) led to the formation of single crystals of zwitterionic H2L as a LiCl adduct, H2L·LiCl·6H2O. The protonation of the secondary amino groups found in this crystal structure points to their high basicity (see the ESI, Fig. S22†).
![]() | ||
Fig. 4 Molecular structure of pc-[Cu(3)] complex found in the crystal structure of pc-[Cu(3)]·Cu(AcO)1.8(tfa)0.2·4H2O·0.5acetone. Hydrogen atoms are omitted for clarity. |
Bond (Å) | pc-[Cu(3)] | cis-O,O′-[Co(L)] | cis-O,O′-[Ni(L)] | pc-[Cu(L)] | trans-O,O′-[Cu(L)]a | trans-O,O′-[Cu(L)]b | cis-O,O′-[Zn(L)] | ||
---|---|---|---|---|---|---|---|---|---|
Mol. 1 | Mol. 2 | Mol. 1 | Mol. 2 | ||||||
a trans-O,O′-[Cu(L)]·NH4(Cl0·54Br0.46). b trans-O,O′-[Cu(L)]·(H3O)(ClO4)·H2O. # Centrosymmetry-related atoms (N8 = N1#, N11 = N4#, O21 = O11#). | |||||||||
M–N1 | 2.102(3) | 2.182(2) | 2.212(2) | 2.154(1) | 2.067(1) | 2.069(1) | 2.068(1) | 2.099(1) | 2.183(1) |
M–N4 | 2.122(3) | 2.115(2) | 2.124(2) | 2.104(1) | 2.017(1) | 2.006(1) | 2.021(1) | 2.024(2) | 2.130(1) |
M–N8 | 2.088(3) | 2.174(2) | 2.189(1) | 2.129(1) | 2.064(1) | 2.069(1)# | 2.068(1)# | 2.099(1)# | 2.217(1) |
M–N11 | 2.119(3) | 2.134(2) | 2.121(2) | 2.083(1) | 2.022(1) | 2.006(1)# | 2.021(1)# | 2.024(2)# | 2.161(1) |
M–O11 | 2.093(3) | 2.094(1) | 2.081(1) | 2.071(1) | 2.148(1) | 2.433(1) | 2.412(1) | 2.372(1) | 2.154(1) |
M–O21 | — | 2.085(1) | 2.109(1) | 2.113(1) | — | 2.433(1)# | 2.412(1)# | 2.372(1)# | 2.080(1) |
Attempts to prepare complexes of H23 with other studied transition metal ions [Co(II), Ni(II) and Zn(II)] by mixing H23 with metal chlorides in aq. MeOH solutions and adding ammonia as a base led to the formation of precipitates insoluble in common solvents which cannot be further studied in solution and, therefore, other study of the complexes was impossible. Different behaviours of the Cu(II) complexes and precipitated phases formed with other transition metal ions come probably from the molecular structures – except for the Cu(II) ion, where a pentacoordinated species with the hydrophilic phosphinate arm pointing out of the hydrophobic coordination sphere is formed, other metal ions prefer an octahedral sphere (see below). In these cases, the metal ions are hexadentately wrapped with the (3)2− anion. Hydrophobic benzyl and trifluoroethyl side groups point away and give to the electroneutral complex species a non-polar character. The molecules are thus hydrophobically packed in the solid state and are intact to the solvent.
All studied transition metal ions, Co(II)–Zn(II), were successfully complexed with H2L. In a typical complexation experiment, an excess of freshly prepared metal(II) hydroxide was reacted with H2L. After several hours, the excess of M(OH)2 was filtered off. As Co(OH)2 could be possibly oxidized, the cobalt(II) complex was prepared by the neutralization of H2L and CoCl2 solution with LiOH or by the reaction of aq. solution of H2L with CoCO3. The absence of the free ligand in solutions of the complexes was confirmed by the 19F NMR spectra. In the spectra, one signal was present in the case of the Co(II)–H2L system but for the other complexes a number of isomeric complex species were obviously initially formed. Heating of the solutions led to spectra with one dominant signal [Ni(II) complex], one broad symmetric signal [Cu(II) complex] and several signals [Zn(II) complex]. The solutions were concentrated and a slow addition of acetone afforded single crystals suitable for structural characterization. For the Co(II), Ni(II) and Zn(II) complexes, crystals contain the cis-O,O′-[M(L)] complex species having a somewhat distorted octahedral sphere; particularly, bond angles related to small five-membered chelate rings are somewhat smaller than 90° (Tables 1 and S2†). In all these complexes, the cyclam conformation cis-V was found.54 All coordinated nitrogen atoms of the macrocycle (N1, N4, N8, N11) have the same stereochemical descriptors according to the Cahn–Ingold–Prelog rules, leading to enantiomeric R,R,R,R and S,S,S,S pairs. Due to crystallographic centrosymmetry, both enantiomers are present in the crystal structures. However, coordination of the phosphinate pendant arm leads to a new stereocentre on the phosphorus atoms. In the solid state, they have the same absolute configuration as the nitrogen atoms of the macrocycle, resulting in the presence of all-N-(R)-all-P-(R) and all-N-(S)-all-P-(S) species.
The cobalt(II) complex crystallizes in the form of cis-O,O′-[Co(L)]·LiCl·3H2O. In the crystal structure, two independent complex molecules are present in the independent unit. However, their geometry is very similar and, therefore, only one of them is shown in Fig. 5. Structural overlay of both independent complex molecules is shown in Fig. S9,† and selected geometric parameters are listed in Tables 1 and S2.†
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Fig. 5 Molecular structure of cis-O,O′-[Co(L)] complex found in the crystal structure of cis-O,O′-[Co(L)]·LiCl·3H2O. Carbon-bound hydrogen atoms are omitted for clarity. |
In the case of the Ni(II)–H2L system, single crystals of the composition cis-O,O′-[Ni(L)]·3.5H2O were isolated. This isomer is stable and is not rearranged to the trans-O,O′ type even on prolonged reflux in an aq. solution, as evidenced by no changes in the 19F NMR spectra. Similar preferential formation of the cis isomer was previously observed for the Ni(II)–H4te2p system.56 The molecular structure of the cis-O,O′-[Ni(L)] complex is very similar to that of the Co(II) complex discussed above (see Tables 1 and S2†) and is shown in Fig. S10.†
From an isomeric mixture of Zn(II) complexes, crystals suitable for diffraction analysis had the composition cis-O,O′-[Zn(L)]·2H2O·0.5acetone. The geometry of the complex species is very similar to that of the Co(II) and Ni(II) complexes discussed above (Fig. S11, Tables 1 and S2†).
If the complexation of Cu(II) proceeds in a slightly acidic solution (pH 3–4) and at a low temperature, a blue isomer is formed exclusively, which was identified by X-ray diffraction as the pentacoordinated species pc-[Cu(L)] with the cyclam conformation trans-I.54 This blue isomer gradually rearranges to the violet one upon prolonged heating (90 °C, 5 d, Fig. S7†) which was identified as trans-O,O′-[Cu(L)] with the cyclam conformation trans-III.54 If the pH used for the complexation reaction was 7.4, a small amount of the trans isomer was formed besides the major pc-[Cu(L)] isomer. Both isomers can be separated by TLC/HPLC. From the mixture, the isomers can be isolated by column chromatography on silica using aq. NH3–EtOH mixture.
The pc-isomer is a kinetic product of the complexation reaction and, at room temperature, it rearranges only very slowly into the trans one, which is obviously the thermodynamic product; a spot of the trans-isomer detectable by TLC appears in a stock solution of the pc-isomer after standing at room temperature for several months. The rearrangement can be completed after refluxing an aq. solution of the pc-isomer for several days (rearrangement is somewhat faster in neutral than in the acidic solution). This isomerism is fully analogous to the behaviour of Cu(II) complexes of 1,8-H4te2p (Fig. 1).39
The molecular structures of both isomers are shown in Fig. 6 and 7. Similarly to the pc-[Cu(3)] species discussed above and to analogous complexes of the 1,8-H4te2p ligand family39 and the recently reported pc-complex with cyclam derivative bearing two [di(phenyl)phosphoryl]methyl pendant arms,57 the pc-[Cu(L)] species adopts an intermediate structure between a trigonal bipyramid and a square pyramid (τ = 0.520).55 The trans-O,O′-[Cu(L)] complex is a tetragonal bipyramid with an axial coordination of the pendant arms elongated by the Jahn–Teller phenomenon. Similar elongation was observed in the related structure of trans-O,O′-[Cu(1,8-H2te2p)].39 Selected geometric parameters of the reported structures are outlined in Tables 1 and S2.†
![]() | ||
Fig. 6 Molecular structure of pc-[Cu(L)] complex found in the crystal structure of pc-[Cu(L)]·3H2O. Carbon-bound hydrogen atoms are omitted for clarity. |
During the preliminary test of kinetic inertness of trans-O,O′-[Cu(L)] (see below), single crystals with the composition trans-O,O′-[Cu(L)]·(H3O)(ClO4)·H2O were crystallized by cooling of a saturated solution of the complex in boiling 1 M HClO4. The formation of this phase clearly indicates the extreme kinetic inertness of the complex. In the crystal structure, the oxonium ion serves as a bridge between non-coordinated oxygen atoms of the pendant arms of two neighbouring trans-O,O′-[Cu(L)] complex molecules (Fig. S12†). However, geometries of the complex species is essentially the same as those observed in the above discussed crystal structure of trans-O,O′-[Cu(L)]·NH4(Cl0.54Br0.46) (Tables 1 and S2†).
Equilibrium | H2Lb | 1,8-H4te2p | Cyclam | H4tetai |
---|---|---|---|---|
a Mixture of isomers (see text).
b This work.
c Ref. 58.
d Overall constant log![]() |
||||
H + L = HL | 11.755(3) | —c,d | 11.29g | 10.52 |
H + HL = H2L | 10.599(3) | 26.41c,d | 10.19g | 10.18 |
Co + L = cis-[Co(L)] | 14.00(8) | 19.28e | 14.3h | 16.38 |
Ni + L = cis-[Ni(L)] | 16.46(8)a | 21.99e | 22.2h | 19.83 |
Cu + L = pc-[Cu(L)] | 22.76(5) | 25.40f | 28.1h | 20.49 |
Zn + L = [Zn(L)] | 15.79(3)a | 20.35e | 15.2h | 16.40 |
Complexation reaction with transition metal ions is relatively slow and, therefore, an out-of-cell method had to be used, with equilibration times of 3 weeks for the Cu(II)–H2L system and 6 weeks for the other ions. Under these conditions, pentacoordinated isomer pc-[Cu(L)] and octahedral cis-isomers of [Co(L)] and [Ni(L)] complexes were formed exclusively, as identified by TLC/HPLC and 19F NMR spectroscopy (see below). However, for the Zn(II)–H2L system, a mixture of at least three isomers was formed according to the 19F NMR spectra. The same mixture of isomers was obtained in independent reactions (see above). According to the Williams–Irving trend, H2L shows a very high selectivity for Cu(II) over its neighbours Ni(II) and Zn(II). The selectivity is about 6–7 orders in magnitude, similarly to that found for related 1,8-disubstituted ligands.39,40,57 Although the stability constants of the complexes are in general somewhat lower than those reported for the cyclam itself, 1,8-H4te2p and H4teta, the stabilities are still sufficient for potential applications as the metal ions are quantitatively complexed under physiological conditions (and the formed complexes are kinetically inert, which is in general more important for possible applications, see below). The Cu(II) ion is fully complexed at pH ∼3, whereas full complexations of Ni(II) and Zn(II) proceed at pH ∼6, and that of Co(II) ion at pH ∼7. The distribution diagrams of the species are shown in Fig. 8.
Overlaid 19F NMR spectra are shown in Fig. 9 for visual comparison (induced shift, linewidth) of the measured 19F NMR signals of the studied complexes.
The 19F NMR spectra of the equilibrated solution of the Co(II)–H2L complex show one broad symmetric signal at −38.6 ppm (Fig. S1†) which agrees with a presence of the cis-O,O′-species found in the solid state. In contrast, in a solution of the Ni(II) complex, three signals were found – a major signal at −47.1 ppm (∼80%) and two equal minor signals at −43.7 and −47.7 ppm (each ∼10%), as shown in Fig. S2.† The pc-[Cu(L)] isomer shows two very broad signals in the 19F NMR spectra as expected for the coordinated and the non-coordinated pendant arms (−52.6 ppm and −53.2 ppm, Fig. S5†), whereas the trans-O,O′-[Cu(L)] isomer shows one symmetric signal (−52.7 ppm, Fig. S6†). In the case of the pc-[Cu(L)] isomer, no coalescence of both signals was observed upon heating. It points that the pentacoordinated sphere is not fluxional. In a solution of the Zn(II) complex, pseudo-quartets (due to F–P,H couplings) centred at −57.15 pm (∼40%), −57.23 ppm (∼55%) and −57.30 ppm (∼5%) were observed (Fig. S3†). An analogous pattern was found also in the 31P NMR spectra (30.1 pm, ∼55%; 29.4 ppm, ∼5%; 28.7 ppm, ∼40%, Fig. S4†). The 31P NMR spectra of other complexes do not show any measurable signals due to the strong paramagnetic effect on the phosphorus atoms.
Based on the numbers of the signals in the 19F NMR spectra, one can conclude that a mixture of isomers is present in the solutions of the Ni(II) and Zn(II) complexes. The assignment of the signals was performed by the measurement of the 19F NMR spectra of freshly dissolved solid samples: batches of crystalline material were prepared from which unit cell parameters were determined for several selected crystals to confirm that they correspond to cis-O,O′-[Ni(L)]·3.5H2O and cis-O,O′-[Zn(L)]·2H2O·0.5(C3H6O), respectively. In the case of the Ni(II) complex, the 19F NMR spectra contains all three signals as described above immediately after dissolution. Thus, an equilibration is evidently very fast process (<3 min). As two minor signals have the same intensity, the pair of minor signals probably corresponds to “all-N-(R) + P-(R,S)” and “all-N-(S) + P-(S,R)” enantiomers formed by a mutual exchange of the coordinated and non-coordinated oxygen atoms of one pendant arm. It seems more accessible than a rearrangement of macrocycle conformation to e.g. conformation trans-III as Ni(II) complexes of cyclam-based ligands are rigid and such a rearrangement is usually energetically demanding and a very slow process.56 In the case of the Zn(II) complex, the situation is much more complicated. Freshly dissolved sample of cis-O,O′-[Zn(L)] with “all-N-(R) + P-(R,R)” and “all-N-(S) + P-(S,S)” configurations shows a multiplet centred at δF = −57.15 ppm (pseudo-quartet due to F–H,P coupling) and δP = 28.69 ppm (quartet due to P–F coupling in 31P{1H} spectra), so these signals can be assigned to the isomer found in the solid state. However, the other two signals increase gradually, and one of them becomes finally dominant. The final equilibrated mixture (5 d, 80 °C) shows the same spectra containing three multiplets as described above for the synthetic mixture and the signal of the original “all-N-(R) + P-(R,R)” and “all-N-(S) + P-(S,S)” enantiomers has finally only 40% abundance.
Obviously, at least two new isomeric complex species are present in the solution. They could be e.g. diastereoisomers “all-N-(R) + P-(R,S)” and “all-N-(R) + P-(S,S)” and their enantiomers as the phosphinate group oxygen atom exchange seems to be the most accessible process. However, some signal overlap has to be supposed as such a mixture should show four individual signals. Alternatively, a partial change of the macrocycle conformation cis-V to other possible conformations could occur; such a process has been documented well for Zn(II) complexes of cyclam derivatives.61
As the complexes of Co(II) and Ni(II) ions show no significant absorption in the near UV region and d–d transition bands have a very low intensity, their kinetic inertness was followed by 19F NMR. Both cis-O,O′-[M(L)] were found to be very inert. The observed half-life of cis-O,O′-[Co(L)] in 1 M HCl at 25 °C was 3.0 h (Fig. S16†). In the case of cis-O,O′-[Ni(L)], no changes in the 19F NMR spectra were found after standing for 24 h under these conditions and, therefore, temperature was increased to 90 °C. At such an increased temperature, the dissociation half-life time was 36 min (Fig. S16†). The inertness of cis-O,O′-[Ni(L)] is thus comparable or somewhat lower than that reported for the trans-O,O′-[Ni(1,8-tfe2cyclam-R2)] family, but significantly higher compared to that of the cis-isomer of Ni(II) complex with 1,8-tfe2cyclam with no coordinating pendant arms (Fig. 1, R = H).32
Distances (Å) | pc-[Cu(3)]a | cis-O,O′-[Co(L)] | cis-O,O′-[Ni(L)] | pc-[Cu(L)]a | trans-O,O′-[Cu(L)]b | trans-O,O′-[Cu(L)]c | cis-O,O′-[Zn(L)] | ||
---|---|---|---|---|---|---|---|---|---|
Mol. 1 | Mol. 2 | Mol. 1 | Mol. 2 | ||||||
a F1–F3 belong to the coordinated pendant arm, F4–F6 belong to the non-coordinated pendant arm. b trans-O,O′-[Cu(L)]·NH4(Cl0.54Br0.46). c trans-O,O′-[Cu(L)]·(H3O)(ClO4)·H2O. # Centrosymmetry-related atoms (F4 = F1#, F5 = F2#, F6 = F3#). $ Fluorine atoms of coordinated/non-coordinated pendant arms. | |||||||||
M⋯F1 | 5.884(3) | 5.570(1) | 5.702(1) | 5.620(1) | 5.813(1) | 5.813(1) | 5.809(1) | 5.904(1) | 5.637(1) |
M⋯F2 | 6.284(3) | 6.266(1) | 6.205(1) | 6.240(1) | 6.338(1) | 6.414(1) | 6.370(1) | 6.377(1) | 6.362(1) |
M⋯F3 | 6.768(3) | 6.484(2) | 6.413(1) | 6.415(1) | 6.701(1) | 6.908(1) | 6.973(1) | 6.993(1) | 6.502(1) |
M⋯F4 | 7.170(3) | 5.815(2) | 5.868(2) | 5.596(1) | 5.075(1) | 5.813(1)# | 5.809(1)# | 5.904(1)# | 5.668(1) |
M⋯F5 | 7.647(3) | 6.330(1) | 6.322(1) | 6.319(1) | 6.590(1) | 6.414(1)# | 6.370(1)# | 6.377(1)# | 6.261(1) |
M⋯F6 | 7.747(3) | 6.634(1) | 6.658(1) | 6.478(1) | 6.966(1) | 6.908(1)# | 6.973(1)# | 6.993(1)# | 6.439(1) |
Average | 6.31/7.52$ | 6.18 | 6.19 | 6.11 | 6.28/6.21$ | 6.38 | 6.38 | 6.42 | 6.14 |
Parameter | H2L | cis-O,O′-[Co(L)] | cis-O,O′-[Ni(L)] | pc-[Cu(L)] | trans-O,O′-[Cu(L)] | cis-O,O′-[Zn(L)]d |
---|---|---|---|---|---|---|
a The pH 8.0 was used to assure the full complexation. b The pH 4.0 was used to avoid formation of the trans-O,O′-isomer. c The pendant arms are not equivalent in the pc-[Cu(L)] complex – one is coordinated, whereas the second is not. However, deconvolution of the measured signal into two peaks −52.6 and −53.2 ppm was possible only at 14.1 T. Both signals are very broad and strongly overlap (Fig. S5†). At lower fields, nearly symmetric signal was observed (Fig. 9). d Mixture of isomers is present in solution; the data are given for the isomer characterized by X-ray crystallography. | ||||||
pH | 7.4 | 8.0a | 7.4 | 4.0b | 7.4 | 7.4 |
19F δ/ppm | −57.13 | −38.6 | −47.1 | −52.9c | −52.7 | −57.15 |
T 1 25 °C (282 MHz)/ms | 1.38(7) × 103 | 35(2) | 3.6(2) | 6.5(3) | 5.1(3) | 1.11(6) × 103 |
T 2 25 °C (282 MHz)/ms | — | 7.2(7) | 2.9(3) | 0.5(1) | 0.7(1) | — |
(T2/T1)282 MHz, 25 °C | — | 0.21 | 0.81 | 0.08 | 0.14 | — |
T 1 37 °C (282 MHz)/ms | 1.79(9) × 103 | 41(2) | 4.5(3) | 8.5(4) | 7.0(4) | 1.42(7) × 103 |
T 2 37 °C (282 MHz)/ms | — | 3.5(3) | 3.1(3) | 0.7(1) | 0.8(1) | — |
(T2/T1)282 MHz, 37 °C | — | 0.09 | 0.69 | 0.08 | 0.11 | — |
T 1 25 °C (376 MHz)/ms | 1.11(5) × 103 | 33(2) | 3.3(2) | 5.9(3) | 5.4(3) | 0.87(4) × 103 |
T 2 25 °C (376 MHz)/ms | 0.90(5) × 103 | 6.3(6) | 2.2(2) | 0.5(1) | 0.9(1) | 0.61(6) × 103 |
(T2/T1)376 MHz, 25 °C | 0.81 | 0.19 | 0.67 | 0.08 | 0.17 | 0.70 |
T 1 37 °C (376 MHz)/ms | 1.29(6) × 103 | 35(2) | 3.6(2) | 8.7(4) | 6.7(3) | 1.04(5) × 103 |
T 2 37 °C (376 MHz)/ms | 0.92(5) × 103 | 4.7(5) | 2.5(2) | 0.6(1) | 1.1(1) | 0.87(4) × 103 |
(T2/T1)376 MHz, 37 °C | 0.71 | 0.13 | 0.69 | 0.07 | 0.16 | 0.84 |
T 1 25 °C (565 MHz)/ms | 0.74(4) × 103 | 28(2) | 3.2(2) | 7.5(4) | 6.1(3) | 0.60(3) × 103 |
T 2 25 °C (565 MHz)/ms | 0.60(3) × 103 | 6.3(6) | 1.9(2) | 0.6(1)/0.8(1) c | 1.2(1) | 0.48(3) × 103 |
(T2/T1)565 MHz, 25 °C | 0.81 | 0.23 | 0.59 | 0.10 | 0.20 | 0.80 |
T 1 37 °C (565 MHz)/ms | 0.94(5) × 103 | 33(2) | 3.9(2) | 9.3(5) | 7.2(4) | 0.77(4) × 103 |
T 2 37 °C (565 MHz)/ms | 0.74(4) × 103 | 3.4(3) | 2.4(2) | 0.7(1)/1.0(1)c | 1.5(1) | 0.62(3) × 103 |
(T2/T1)565 MHz, 37 °C | 0.79 | 0.10 | 0.62 | 0.09 | 0.21 | 0.81 |
The cis-O,O′-[Co(L)] species showed longitudinal relaxation times in the range 30–40 ms which is very convenient for practical utilization. It is ca. 2–3 times longer (at the same magnetic fields and temperatures) compared to that of Co(II) complexes of 1,8-tfe2-cyclams (Fig. 1, R = CH2CO2H, CH2PO3H2) studied previously.34 The difference comes from longer distances between the central metal ion and fluorine atoms in cis-O,O′-[Co(L)] when compared to that in the complexes of 1,8-tfe2-cyclams (6.19 Å and 5 bonds for cis-O,O′-[Co(L)] compared to 5.25 Å and 4 bonds for Co(II)–1,8-tfe2-cyclams). Furthermore, the 19F NMR signal is relatively narrow (half-width 40–90 Hz depending on the temperature and magnetic field used) when compared to other studied paramagnetic complexes {Ni(II) 100–170 Hz, pc-[Cu(L)] 370–640 Hz, trans-O,O′-[Cu(L)] 200–450 Hz}, although in combination with a relatively long T1 it gives a rather low /T1 ratio (0.1–0.2).
The 19F NMR signal of cis-O,O′-[Ni(L)] relaxes significantly faster than that of the Co(II) complex but it shows ca. 2-times slower relaxation (T1 ∼3–4 ms) in comparison with that of the Ni(II) complexes of 1,8-tfe2-cyclam derivatives (Fig. 1, R = H, CH2CO2H, CH2PO3H2, (CH2)2NH2, pyrid-2-ylmethyl), whose T1 was typically in range of 1–2 ms.31,32 It corresponds to the distance change (average M⋯F 6.11 Å for the cis-O,O′-[Ni(L)] complex compared to 5.16–5.34 for the Ni(II)–1,8-tfe2-cyclam complexes). The relaxation time is still too short for a comfortable standard imaging, but the high /T1 ratio 0.6–0.8 of the signal can be potentially utilized in special imaging experiments.63,64 For the agent useful in standard imaging, a longer separation of the metal ion and fluorine atoms is obviously needed when using Ni(II) ion, as evidenced by T1 in the order of tens of milliseconds observed for Ni(II) complexes of cross-bridged cyclam containing [(trifluoromethyl)phenyl]acetamide pendant arms (Fig. 1, 8 bond separation, 7.28 Å, 10 ms; 9 bond separation, 8.72 Å, 29 ms).33
Observed T1 for the Cu(II)–H2L complexes (ca. 5–9 ms) is slightly lower than values found for isomeric Cu(II) complexes of 1,8-(tfe-NHCH2CH2)2cyclam (7–12 ms)42 whereas the average M⋯F distances found in the Cu(II)–H2L complexes are somewhat longer (6.36 Å) than those observed for the Cu(II)–1,8-(tfe-NHCH2CH2)2cyclam (5.6–6.1 Å).42 However, the signals of the Cu(II)–H2L complexes are very broad. The /T1 ratio is ca. 0.1 for the pentacoordinated and ca. 0.2 for the trans-O,O′-[Cu(L)] isomer, respectively.
The T1 data acquired at 25 °C have been further assessed using the equation set of the Bloch–Redfield–Wangsness theory.30 Preliminary calculation confirmed that the contribution of Curie relaxation is for the presented set of complexes negligible and, thus, only the dipolar relaxation mechanism was considered. This phenomenon is quantified by eqn (1):
![]() | (1) |
τc−1 = τe−1 + τR−1 | (2) |
Of the used paramagnetic metal ions, the situation is the most straightforward for the Co2+ complex, as τe of this ion is significantly shorter than τR (by ca. 2 orders of magnitude) and, thus, τc is governed dominantly by τe. In contrast, for Ni2+ and Cu2+, contributions of both τe and τR to τc are significant, and thus, their values significantly correlate (i.e. a slight change in the suggested τR brings a significant change in τe, and vice versa).
Footnote |
† Electronic supplementary information (ESI) available: NMR spectra of studied complexes, colour change of isomeric Cu(II) complexes, experimental data and details for the crystal structure refinement, ligand distribution diagram, details of the kinetic inertness study, NMR characterization of organic compounds, and discussion of the crystal structures of synthetic intermediates. CCDC 2262037–2262048. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3dt01420g |
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