Ultrafast Ligand Self-Exchanging Gadolinium Complexes in Ionic

Feb 8, 2018 - NMR field probes for MRI require high densities of chemically equal fluorine and paramagnetic ions such as Gd3+. ... On the Magnetic Cou...
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Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Ultrafast Ligand Self-Exchanging Gadolinium Complexes in Ionic Liquids for NMR Field Probes Anna Looser,† Christoph Barmet,‡,§ Thomas Fox,† Olivier Blacque,† Simon Gross,‡ Jennifer Nussbaum,‡ Klaas P. Pruessmann,*,‡ and Roger Alberto*,† †

Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland Institute for Biomedical Engineering, ETH Zurich and University of Zurich, Gloriastrasse 35, CH-8092 Zurich, Switzerland § Skope Magnetic Resonance Technologies AG, Gladbachstrasse 105, CH-8044 Zurich, Switzerland ‡

S Supporting Information *

ABSTRACT: Concurrent magnetic field monitoring in MRI with an array of NMR field probes allows for reducing image imperfections. High 19F concentrations together with short relaxation times are basic probe properties. We present the NMR properties of [Gd(NTf2)4]− dissolved in an ionic liquid consisting of an imidazolium cation and the [NTf2]− anion. These solutions achieve fluorine concentrations as high as 26 M and rapid relaxation times in the sub-ms time range. The second order self-exchange rate of coordinated [NTf2]− with [NTf2]− as determined with [Y(NTf2)4]− is 4.5 × 105·M−1·s−1. X-ray structure analyses confirm the coordination number of eight around Gd3+ and Y3+. These ionic-liquid solutions are thus excellent candidates for dynamically probing the NMR fields in MRI.

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another nucleus, the best option being 19F due to its favorable gyromagnetic ratio.5 To yield coherent output of an adequate signal-to-noise ratio, 19F nuclei in the probe liquid must be all magnetically equivalent and of high density on the order of tens of M. In existing implementations, this is achieved with perfluorinated organic compounds such as hexafluorobenzene, doped with a relaxation agent to accelerate probe recovery after each field readout. Concurrent field measurement with such probes has recently enabled a range of promising applications.5−9 In efforts to improve further the versatility of field recording during MRI, the next key challenge is to render it fully continuous. The need for probe recovery between excitations causes dead time, and probe signals may fade upon dephasing in strong, sustained gradient fields. A system that overcomes these interruptions was recently created from 1H field probes using water droplets.10 It achieves continuity of field measurement by rapid alternation between probes with very short relaxation times (25 M [19F] limit. Among the described ILs, imidazolium-based ones with NTf2− approach these properties best.28 The IL [amim][NTf2] (amim+ = 1-allyl-3-methyl-1H-imidazol-3-ium) has a viscosity η = 40 mPa·s (20 °C) and a fluoride concentration [F] of 22.7 M according to its density of ρ = 1.524 g/mL. We focused our studies on this IL, and some additional results with [emim][NTf2] (emim+ = 1-ethyl-3-methyl-1H-imidazol-3-ium) are given in the Supporting Information. Ln3+ complexes undergo generally fast dissociative ligand self-exchange, especially with weakly coordinating anions or

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RESULTS AND DISCUSSION Gadolinium, as a middle lanthanide element, is of typical hard character and displays generally complexes with coordination numbers of 8−9. Its complexes with a multidentate ligand and one or more coordinated water molecules are key as MRI contrast agents.11,12 The principle behind the applicability of these agents is the rapid exchange of coordinated water molecules for allowing magnetization transfer to bulk water.13 In contrast to in vivo applications of Gd3+ complexes, NMR field probes as described in the introduction require complexes that exchange their homoperfluorinated ligands rapidly with the bulk ionic-liquid solvent. Therefore, Gd3+ complexes with weakly coordinating anionic ligands are key for our purpose.14 At the same time, these anions should be perfluorinated and form ionic liquids15 in order to ensure one single 19F signal. These criteria reduce the selection of anions substantially. Bis(trifluoromethylsulfonyl)imide (NTf2−) is particularly convenient due to its potential bidentate coordination mode. Only a limited number of homoleptic d- or f-element complexes with NTf2− as ligands have been reported, among them one with Co2+,16 Yb2+ and with Nd3+, Tb3+, Tm3+, and Lu3+.17,18 Binary gadolinium complexes with weakly coordinating anions (A−) as ligands can be prepared by protonation of basic L in GdL3 type precursors with the respective conjugate acid HA. Concomitant ligand exchange leads to desired GdA3.19 Accordingly, we prepared in a first step [Gd(bta)3] (1, bta = bis(trimethylsilyl)amide) from an anion metathesis reaction in THF between GdCl3 and Li[bta].20 The reaction between 1 and the strong acid Tf2NH gave the complex [Gd(NTf2)3] (2), which could be isolated as a white powder in a clean reaction (Scheme 1). Complex 2 is very soluble in triflimide-based IL (vide infra). Due to its coordinatively unsaturated state, we hypothesized that 2 will form in the IL a complex with a coordination number higher than six, as implied by the stoichiometric formula. To support this hypothesis, we reacted 2 with 1 eq of [NnBu4](NTf2) in dichloromethane or tetrachloroethane.21 After very slow evaporation of the solvent over days in the glovebox, crystals of quality for X-ray diffraction structure analysis could be grown, which confirmed its structure; 2 extended its coordination sphere from six to B

DOI: 10.1021/acs.inorgchem.7b03191 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

Figure 1. ORTEP of [NnBu4][Gd(NTf2)4] (3, left) and [Gd(NTf2)3(HO-iPr)3] (4, right). Cations omitted and fluorides shown as spheres for clarity. The transoid and cisoid configurations in 3 and 4, respectively, are visible for the [NTf2−] ligands. Ellipsoids except for fluorides are drawn on the 30% probability level (see Supporting Information for details).

components around a chemical shift of −81.7 ppm (Figure 3). The high field component could be attributed to the complex ligands based on the comparison with mixtures containing other complex/IL ratios. At 185 K, the calculations indicate two different 19F shifts for the complex ligands with a separation of 0.46 ppm and an inherent line width of around 180 Hz. It is remarkable that the higher populated complex ligands exhibit an unambiguously broader line than the less populated free ligands (population ratio 4:1.5). One possible explanation is still that fast intramolecular dynamic processes occur between different complex sites, whereas intermolecular exchange with the free ligands is already slow. Anisotropy effects can be another reason, because they might be stronger in the larger and less symmetric complex as compared with the free ligands. With regard to these uncertainties and especially to the unknown exchange mechanism, the calculated rates as well as the resulting activation barrier (see below) can just be approximate values. However, at any time, the observed 19F line patterns did not exceed a total width of 450 Hz. This value is small, compared to the line broadening effects within paramagnetic complexes, which are in addition resolved in highly viscous IL. Therefore, line splittings, which are, in analogy to 6, potentially also expected for solutions of 2 in IL, are unlikely and actually not observed, since they are wiped out by much stronger effects of paramagnetism and viscosity. This results in single 19F resonances and complies well with an important criterion for accurate MRI calibration (for a temperature dependence study with [emim][NTf2], see Supporting Information). An Arrhenius analysis of the obtained rate constants according to Figure 3 yields a pre-exponential constant of about 109 s−1, an activation barrier of ∼24 kJ/mol, and a second order rate constant kex at r.t. of 4.5 × 105·M−1·s−1. In undiluted IL, the pseudo first order exchange constant is thus well below the μs range (see Supporting Information). For evaluating the utility of Gd3+/IL solutions for an NMR field probe application, we investigated their T1 and T2 dependencies on concentration and viscosity. When [Gd3+] is kept constant at 0.1 M under successive decrease of [F−]IL and viscosity by dilution with CH2Cl2, relaxation times display the trends that are depicted in Figure 4 (left). Without dilution with CH2Cl2 ([F] = 23 M), the observed T1 time of 1.8 ms is long compared with T2 of 0.17 ms. Upon dilution, viscosity decreases, and T1 reduces to 0.4 ms, accompanied by just a

neutral molecules such as water.29−32 For an estimation of the NTf2− self-exchange rate within the paramagnetic Gd 3+ complex 3 via NMR, we chose the analog but diamagnetic Y3+ complex, since both lanthanoides have comparable ionic radii.12 The complex [Y(NTf2)3] (6) was prepared in the same way as 2 via [Y(bta)3] (5) and crystallized in the presence of excess [NnBu4][NTf2]. The structure of the resulting complex [NnBu4][Y(NTf2)4] (7) could be solved and is, in agreement with the similarity of Y3+ and Gd3+, isostructural to 3 (see Supporting Information). Thus, we recorded temperature dependent 19F NMR spectra of the model complex 7 in diluted mixtures with the IL in order to monitor the ligand exchange and to calculate the exchange rates on the base of line shape analysis with the program gNMR. Solutions of the gadolinium complex 3 in pure IL are not suitable for this purpose, since its strong paramagnetism and the temperature dependent viscosity of the IL solvent wipe out the influence of dynamic effects onto the line shapes. The room temperature 19F NMR spectra of solutions of 6 and [amim][NTf2] in d6-acetone show different signals at −80.35 and −80.41 ppm, respectively (Figure 2a,b). A 1:1

Figure 2. Room temperature, 470.67 MHz 19F NMR spectra (d6acetone) of 0.1 M Y(Tf2N)3 6 (a), 0.1 M ionic liquid [amim][NTf2] (b), and a (1:1) 0.1 M mixture of both (c).

mixture displays just one sharp resonance for free and bound NTf2− at −80.36 ppm (Figure 2c), indicating the expected fast exchange between these two components on the NMR time scale. The 19F resonances of diluted solutions of 6 and IL in CD2Cl2 after cooling from 233 to 185 K show successive line broadening, coalescence, and splitting into two distinguishable C

DOI: 10.1021/acs.inorgchem.7b03191 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

Figure 3. 19F NMR (282.39 MHz) spectra of a mixture of 6 with [amim][NTf2] (1:1.5) in CD2Cl2 at different temperatures. Top parts: observed spectra; bottom parts: calculated line shapes at appropriate exchange rate [Hz].

Figure 4. 19F T1 and T2 relaxation times of [Gd(NTf2)3] (2) in the ionic liquid [amim][[NTf2]; 0.1 M [Gd3+] in IL diluted with dichloromethane to the indicated fluoride concentration (left) and over a range of concentrations of 2 in pure ionic liquid at 298 and 313 K (right).

slight T2 increase. However, after dilution, [F−] amounts to just 8 M, which is too low for useful field probes. Alternatively, a variation of the complex concentration in undiluted IL has been checked in order to accelerate T1 relaxation (Figure 4, right). Due to increasing complex concentrations up to 0.46 M and growing paramagnetic influences, T1 and T2 reach values of 0.5 and 0.04 ms, respectively, along with a total fluorine concentration of up to 25.6 M (density 2.125 g/cm3, for details, see Supporting Information) Overall, the proposed Gd3+/IL solutions offer a highly interesting system for use as NMR field probes. With achieved T1 and T2 times down to the sub-ms range, and fluoride concentrations of up to 25 M, it enables rapid probe reexcitation and continuous field observation with alternating sets. In comparison, previously deployed systems based on Cr(TMHD)3 dissolved in hexafluorobenzene exhibited minimal T1 and T2 times of 77 and 47 ms, respectively, and were thus unsuitable for such use.3 Moreover, the proposed system offers the flexibility of fine-tuning both T1 and T2 over a wide range to match the requirements of specific applications. Here, lower signal intensity due to the reduction of fluoride concentration must not necessarily decrease net field sensitivity, since its effect can be compensated by equally lowered T1/T2 ratios, exhibiting favorable steady-state signal intensity at rapid probe operation. Figure 4 reflects an expected T1 and T2 relaxation behavior upon temperature and concentration changes. Both T1 and T2

are steered by molecular reorientation rates, which directly depend on the viscosity of the medium. At reduced temperatures and a lower degree of IL dilution, viscosity increases with the consequence of reduced molecular mobility. This leads to less efficient T1 relaxation, in particular for high frequency NMR nuclei like 19F (ω = 282 MHz): the decreasing molecular tumbling frequency τc−1 then reaches values far below ω/0.62 (i.e., average tumbling rate for most efficient T1 relaxation). On the other hand, at low tumbling rates, electron−nuclear dipolar couplings are less efficiently suppressed by averaging effects, and therefore, T2 relaxation is accelerated. Moreover, at high Gd concentrations, the observed T2 relaxation times show no significant temperature dependence (Figure 4, right). This is consistent with the assumed pseudo first order nature of the ligand self-exchange, which is not diffusion controlled and, therefore, less dependent on the viscosity, since the free ligands of the IL solvent are densely packed in the second (and third) coordination sphere of the metal center.

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CONCLUSION Solutions of Gd3+ complexes with homoperfluorinated, anionic ligands in ILs that comprise the fluorinated ligands achieve T1/ T2 relaxation times in the sub-ms range. Therefore, the concept of dissolving ultrafast ligand self-exchanging paramagnetic complexes in undiluted IL is more promising than the use of D

DOI: 10.1021/acs.inorgchem.7b03191 Inorg. Chem. XXXX, XXX, XXX−XXX

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(3) De Zanche, N.; Barmet, C.; Nordmeyer-Massner, J. A.; Pruessmann, K. P. NMR probes for measuring magnetic fields and field dynamics in MR systems. Magn. Reson. Med. 2008, 60, 176−186. (4) Barmet, C.; De Zanche, N.; Pruessmann, K. P. Spatiotemporal magnetic field monitoring for MR. Magn. Reson. Med. 2008, 60, 187− 197. (5) Vannesjo, S. J.; Wilm, B. J.; Duerst, Y.; Gross, S.; Brunner, D. O.; Dietrich, B. E.; Schmid, T.; Barmet, C.; Pruessmann, K. P. Retrospective Correction of Physiological Field Fluctuations in High-Field Brain MRI Using Concurrent Field Monitoring. Magn. Reson. Med. 2015, 73, 1833−1843. (6) Wilm, B. J.; Nagy, Z.; Barmet, C.; Vannesjo, S. J.; Kasper, L.; Haeberlin, M.; Gross, S.; Dietrich, B. E.; Brunner, D. O.; Schmid, T.; Pruessmann, K. P. Diffusion MRI with Concurrent Magnetic Field Monitoring. Magn. Reson. Med. 2015, 74, 925−933. (7) Kasper, L.; Haeberlin, M.; Dietrich, B. E.; Gross, S.; Barmet, C.; Wilm, B. J.; Vannesjo, S. J.; Brunner, D. O.; Ruff, C. C.; Stephan, K. E.; Pruessmann, K. P. Matched-filter acquisition for BOLD fMRI. NeuroImage 2014, 100, 145−160. (8) Gross, S.; Barmet, C.; Dietrich, B. E.; Brunner, D. O.; Schmid, T.; Pruessmann, K. P. Dynamic nuclear magnetic resonance field sensing with part-per-trillion resolution. Nat. Commun. 2016, 7, 13702. (9) Gross, S.; Vionnet, L.; Kasper, L.; Dietrich, B. E.; Pruessmann, K. P. Physiology Recording with Magnetic Field Probes for fMRI Denoising. NeuroImage 2017, 154, 106−114. (10) Dietrich, B. E.; Brunner, D. O.; Wilm, B. J.; Barmet, C.; Pruessmann, K. P. Continuous Magnetic Field Monitoring Using Rapid Re-Excitation of NMR Probe Sets. IEEE T. Med. Imaging 2016, 35, 1452−1462. (11) Hermann, P.; Kotek, J.; Kubicek, V.; Lukes, I. Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes. Dalton Trans. 2008, 23, 3027−3047. (12) Helm, L.; Merbach, A. E. Inorganic and bioinorganic solvent exchange mechanisms. Chem. Rev. 2005, 105, 1923−1959. (13) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Gadolinium(III) chelates as MRI contrast agents: Structure, dynamics, and applications. Chem. Rev. 1999, 99, 2293−2352. (14) Krossing, I.; Raabe, I. Noncoordinating anions - Fact or fiction? A survey of likely candidates. Angew. Chem., Int. Ed. 2004, 43, 2066− 2090. (15) Freudenmann, D.; Wolf, S.; Wolff, M.; Feldmann, C. Ionic Liquids: New Perspectives for Inorganic Synthesis? Angew. Chem., Int. Ed. 2011, 50, 11050−11060. (16) Nockemann, P.; Pellens, M.; Van Hecke, K.; Van Meervelt, L.; Wouters, J.; Thijs, B.; Vanecht, E.; Parac-Vogt, T. N.; Mehdi, H.; Schaltin, S.; Fransaer, J.; Zahn, S.; Kirchner, B.; Binnemans, K. Cobalt(II) Complexes of Nitrile-Functionalized Ionic Liquids. Chem. Eur. J. 2010, 16, 1849−1858. (17) Mudring, A.-V.; Babai, A.; Arenz, S.; Giernoth, R. The “Noncoordinating” Anion Tf2N− Coordinates to Yb2+: A Structurally Characterized Tf2N− Complex from the Ionic Liquid [mppyr][Tf2N]. Angew. Chem., Int. Ed. 2005, 44, 5485−5488. (18) Babai, A.; Mudring, A. V. The first homoleptic bis(trifluoromethanesulfonyl)amide complex compounds of trivalent felements. Dalton T. 2006, 1828−1830. (19) Beck, W.; Suenkel, K. Metal complexes of weakly coordinating anions. Precursors of strong cationic organometallic Lewis acids. Chem. Rev. 1988, 88, 1405−1421. (20) Bradley, D. C.; Ghotra, J. S.; Hart, F. A. Low co-ordination numbers in lanthanide and actinide compounds. Part I. The preparation and characterization of tris{bis(trimethylsilyl)-amido}lanthanides. J. Chem. Soc., Dalton Trans. 1973, 1021−1023. (21) Bortolini, O.; Chiappe, C.; Ghilardi, T.; Massi, A.; Pomelli, C. S. Dissolution of Metal Salts in Bis(trifluoromethylsulfonyl)imide-Based Ionic Liquids: Studying the Affinity of Metal Cations Toward a “Weakly Coordinating” Anion. J. Phys. Chem. A 2015, 119, 5078− 5087. (22) Babai, A.; Mudring, A.-V. Anhydrous Praseodymium Salts in the Ionic Liquid [bmpyr][Tf2N]: Structural and Optical Properties of

saturated solutions of complex ligand mixtures in innocent solvents, which are in addition volatile and less convenient for practical use. Ternary mixtures of cation, ligand, and paramagnetic centers achieve physical properties and fluorine concentrations that are indispensable for reliable NMR field sensing. The actually described complex [Gd(NTf 2 ) 3 ] possesses in this respect the most favorable properties reported so far, as its ligand self-exchange in [amim][NTf2] as well as in [emim][NTf2] is fast, resulting in sub-ms 19F relaxation times together with high fluorine concentrations and the appearance of just one 19F signal, and enables a range of applications based on short-lived fluorine sensors including continuous field observation. The desired high fluoride concentrations require small cation sizes and/or more −CF3 groups per anion. Compared with the described allyl- and ethyl-methylimidazolium cations, [PR3R′]+ or other alkyl-methyl-imidazolium cations are associated with significantly smaller fluorine concentrations due to their larger size. Fluorine concentrations are then in the range of just 13 M as for, e.g., [P(nBu)3(C2H4OC2H4OCH3)+], compared to 23 M for [amim][[NTf2].

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b03191. General information concerning experimental procedures and syntheses and characterization data, additional figures for T1/T2 dependencies on viscosity and temperature for [emim][NTf2], and crystal data for complexes 3, 4, and 7 (PDF) Accession Codes

CCDC 1531945, 1557761, and 1587081 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (R.A.) *E-mail: [email protected] (K.P.P.) ORCID

Roger Alberto: 0000-0001-5978-3394 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the Swiss National Science Foundation SNFS (project 200021_155996/1) and the University of Zurich for financial support.

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DOI: 10.1021/acs.inorgchem.7b03191 Inorg. Chem. XXXX, XXX, XXX−XXX