Jan Blahut

Ladislav Benda

Jan Kotek

Guido Pintacuda

Petr Hermann

Paramagnetic Cobalt(II) Complexes with Cyclam Derivatives: Towards 19 F MRI Contrast Agents

Keywords: paramagnetic NMR, high-spin cobalt complexes, macrocyclic complexes, phosphonate complexes, cyclam derivatives, kinetic inertness, hyperfine shift calculations, spin density delocalization, 19 F MRI contrast agents, NMR relaxation

In order to develop novel, more efficient and/or selective contrast agents for magnetic resonance imaging (MRI), different modi operandi are explored as alternatives to water-relaxation enhancement. In this work, cobalt(II/III) complexes of bis(N-trifluoroethy)cyclam derivatives with two acetate or two phosphonate pendant arms, H2te2f2a and H4te2f2p, were prepared and investigated. X-ray diffraction structures confirmed octahedral coordination with a very stable trans-III cyclam conformation and with fluorine atoms located about 5.3 Å from the metal center. The Co(II) complexes are kinetically inert, decomposing slowly even in 1 M aqueous HCl at 80 °C. The Co(II) complexes exhibited well-resolved paramagnetically-shifted NMR spectra.

These were interpreted with the help of quantum chemistry calculations. The 13 C NMR shifts of the trans-[Co II (te2f2p)] complex were successfully assigned based on spin density delocalization within the ligand molecule. The obtained spin density also helps to describe d-metal-induced NMR relaxation properties of 19 F nuclei, including the contribution of a Fermi contact relaxation mechanism. The paramagnetic complexes show convenient relaxation properties to be used as 19 F MRI contrast agents.

Introduction

Complexes of d-and f-elements with macrocyclic ligands are broadly used in diverse applications. Their stability/inertness, as well as reliably defined spectroscopic and magnetic properties, make them well-suited for utilization in medicine and molecular biology. [1][2][3][START_REF] Hermann | Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes[END_REF][5][6][START_REF] Nitsche | Pseudocontact shifts in biomolecular NMR using paramagnetic metal tags[END_REF] The complexes of macrocyclic chelators are used in diagnostic medicine for various imaging modalities. The most common imaging techniques involve positron emission tomography (PET) with metal radioisotopes, as 68 Ga, [START_REF] Neese | The ORCA program system[END_REF] Cu or 89 Zr, (Ref. 8) optical imaging with fluorescent lanthanide(III) ions 6 and magnetic resonance imaging (MRI) employing complexes of trivalent gadolinium. [1][2][3][START_REF] Hermann | Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes[END_REF][5] Recently, complexes of metal ions other than Gd(III), e.g. divalent manganese or iron, have been investigated as contrast agents (CAs) for "classical" MRI based on imaging of water protons in tissues. 9,10 For many prospective MRI applications, a highly quantitative response and "hot-spot" background-free information are required, in parallel with higher sensitivity of the MRI CAs to environmental changes in tissue. Several methods were developed including paramagnetic chemical exchange saturation transfer (PARACEST), 11 detection of paramagnetically shifted 1 H nuclei present in the CAs (PARASHIFT) [START_REF] Schmidt | Highly shifted proton MR imaging: Cell tracking by using direct detection of paramagnetic compounds[END_REF][13][START_REF] Harnden | Employing paramagnetic shift for responsive MRI probes[END_REF] and utilization of 19 F. [START_REF] Tirotta | F Magnetic resonance imaging (MRI): From design of materials to clinical applications[END_REF][START_REF]Fluorine Magnetic Resonance Imaging[END_REF][START_REF] Peterson | Fluorinated paramagnetic complexes: Sensitive and responsive probes for magnetic resonance spectroscopy and imaging[END_REF][START_REF] Xie | F magnetic resonance activity-based sensing using paramagnetic Metals[END_REF] These emerging CAs have mostly relied on paramagnetic lanthanide(III) ions while transition metal ions have been involved only very recently. The complexes of d-metal ions have been developed for application as PARACEST [19][START_REF] Srivastava | Eight-Coordinate, stable Fe(II) complex as a dual 19 F and CEST contrast agent for ratiometric pH imaging[END_REF][START_REF] Harris | Dramatic enhancement in pH sensitivity and signal intensity through ligand modification of a dicobalt PARACEST probe[END_REF][START_REF] Yu | Highly fluorinated metal complexes as dual 19 F and PARACEST imaging agents[END_REF][START_REF] Pradhan | Seven coordinate Co(II) and six coordinate Ni(II) complexes of an aromatic macrocyclic triamide ligand as paraCEST agents for MRI[END_REF] or PARASHIFT 24 contrast agents and for 19 F-MRI. [START_REF] Blahut | Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for 19 F magnetic resonance imaging[END_REF][START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF][27][START_REF] Pujales-Paradela | Reinforced Ni(II)-cyclam derivatives as dual 1 H/ 19 F MRI probes[END_REF] The transition metal containing 19 F-MRI contrast agents have been used as responsive probes. [START_REF] Xie | F magnetic resonance activity-based sensing using paramagnetic Metals[END_REF][START_REF] Yu | Highly fluorinated metal complexes as dual 19 F and PARACEST imaging agents[END_REF]29 The mostly utilized metal ions are divalent iron, cobalt or nickel. Chemical, biochemical and magnetic properties of these complexes are often more favourable than those of more commonly utilized complexes of trivalent lanthanides. However, the relation between three-dimensional molecular structure, electronic structure and MRI CA efficiency of macrocyclic complexes is much less understood for transition metal ions than for trivalent lanthanides. The accessibility of reliable experimental data is, therefore, critical. Nuclear magnetic resonance spectroscopy (NMR) as the most versatile method for studying molecules in solution is used for paramagnetic systems as well (paramagnetic NMR, pNMR). [START_REF] Bertini | NMR of Paramagnetic Molecules[END_REF][START_REF] Pell | Paramagnetic NMR in solution and the solid state[END_REF] In the MRI CA, however, the proximity of paramagnetic metal ion to the observed nucleus has an enormous impact on its NMR shift and relaxation properties. Due to these effects, coherence transfers are often not efficient and multidimensional correlation experiments are thus extremely difficult.

Assignment and interpretation of large pNMR shifts relies therefore uniquely on 1D spectra and can be difficult or even impossible without additional information. Such additional information is available from quantum chemistry (QC) modelling. Modern formulation [START_REF] Heuvel | NMR chemical shift in an electronic state with arbitrary degeneracy[END_REF][START_REF] Vaara | Magnetic couplings in the chemical shift of paramagnetic NMR[END_REF] of Kurland-McGarvey theory of paramagnetically-induced shifts [START_REF] Kurland | Isotropic NMR shifts in transition metal complexes: The calculation of the Fermi contact and pseudocontact terms[END_REF] allows assignment and interpretation of pNMR spectra in systems with strong spin-orbit coupling such as Co(II) complexes. The pNMR shift calculations provide a direct link between the geometry of a transition metal complex, its electronic structure and the experimental NMR data. This synergistic pNMR/QC approach has recently been applied to Co(II) centers in small organometallic complexes [START_REF] Rouf | 1 H chemical shifts in paramagnetic Co(II) pyrazolylborate complexes: A first-principles study[END_REF] and in metalloproteins. [START_REF] Benda | Pseudocontact NMR shifts over the paramagnetic metalloprotein CoMMP-12 from first principles[END_REF] In this article, we characterize a series of paramagnetic Co(II) complexes in solution by a combination of NMR spectroscopy and theoretical calculations. Due to their promising chemical and relaxation properties, the studied complexes are proposed as new fluorine MRI CAs.

Results and discussion

Complex synthesis and stability

The ligands, H4te2f2p and H2te2f2a (Scheme 1), were obtained by published method. [START_REF] Blahut | Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for 19 F magnetic resonance imaging[END_REF][START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF] The macrocycle amine groups have to be deprotonated (logK1,2 10.86 and 10.09) to allow their coordination and the final complex formation. [START_REF] Blahut | Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for 19 F magnetic resonance imaging[END_REF] complexes, where a cis-V structure was suggested for the intermediate (see Chart S1 for the cyclam conformations in complexes). [START_REF] Blahut | Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for 19 F magnetic resonance imaging[END_REF][START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF] The trans-[Co II (te2f2p)] 2-complex was formed without any observable intermediate (τ½ = 0.18 h at 70 °C; Figure S2). In water, the neutral trans-[Co II (te2f2a)] complex is poorly soluble. The trans-[Co II (te2f2p)] 2-is soluble only as a dianion at pH > 6.5.

Both complexes are exceptionally stable against acidic hydrolysis (Table S1). ] 2-, respectively). [START_REF] Blahut | Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for 19 F magnetic resonance imaging[END_REF][START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF] Such a large difference between the Co(II) and Ni(II) variants of the complex is expected, taking into account higher thermodynamic stabilization of the d 8 electronic configuration compared to the d [START_REF] Nitsche | Pseudocontact shifts in biomolecular NMR using paramagnetic metal tags[END_REF] one according the Irving-Williams series.

Counter-intuitively, the prepared cobalt(II) complexes are not sensitive to air oxygen, neither in the solid state nor in aqueous solution (no oxidation was observed within water potential window by cyclic voltametry). Such a resistance to oxidation has already been reported for several Co(II) complexes with macrocyclic ligands. [START_REF] Dorazio | CoCEST: cobalt(II) amideappended paraCEST MRI contrast agents[END_REF] To obtain diamagnetic trivalent cobalt complexes, solid meta-chloroperoxybenzoic acid (m-CPBA) was used as an oxidant. The m-CPBA is insoluble in water and, thus, the reaction was performed heterogeneously with the added advantage that excess m-CPBA and products of its reduction are easily removed by filtration. It should be noted that decomposition of the ligand (te2f2p) [START_REF] Hermann | Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes[END_REF]-was observed when the oxidation was carried out with hydrogen peroxide instead of m-CPBA. Cleavage of the C-P bond in the N-C-P fragment has been reported under such conditions. [START_REF] Drabowicz | Reactivity of aminophosphonic acids. Oxidative dephosphonylation of 1-aminoalkylphosphonic acids by aqueous halogens[END_REF] Both trans- compared to those of N-trifluoroethyl as a result of their higher nucleophilicity and coordination stabilization through formation of the axial chelate ring. This feature is consistent with the data previously observed for the analogous Ni(II) complexes. [START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF] The octahedral shape of all complexes is only negligibly distorted, mainly due to steric demands of the chelate rings formed by the macrocycle amino groups, with the N-Co-O angles of the five-membered rings and the N-Co-N angles of the six-membered rings only slightly deviating from 90°. The average Co•••F distances (Table 1) in the Co II complexes, a crucial parameter for the 19 F relaxation enhancement, are 5.24 and 5.26 Å complexes with acetate-and phosphonate-containing ligands, respectively. The parameters are similar to those observed previously for the Ni(II) analogues (5.22-5.23 Å). [START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF] The average Co•••F distance in the Co III complex, 5.14 Å , is slightly shorter than those found in the divalent metal ion complexes. = 1.503-1.536 Å] pointing to a phosphoryl (P=O) character of these bonds (Figure 2). The oxygen atom O12A is protonated and the corresponding hydrogen atom was fully refined. It is stabilized by a short hydrogen bond to oxygen atom O12B# from the neighboring molecule:

d(O12A-H12A) 0.96, d(H12A•••O12B#) 1.51, d(O12A•••O12B#) 2.468 Å and Ð(O12A- H12A•••O12B#) 177°.
The hydrogen bond slightly elongates also P1B-O12B bond to 1.536 Å comparing to the remaining ones. The monoprotonated coordinated ligand (Hte2f2p) 3-was also found in the structure of the analogous Ni(II) complex [START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF] as well as in some complexes of divalent metal ions with several methylphosphonate cyclam derivatives. 40 a For centrosymmetric molecules: N1B = N1#, N4B = N4#, O11B = O11#; # means symmetryrelated atoms.

Magnetometry and paramagnetic NMR spectroscopy

According to the bulk magnetic susceptibility measurement of a trans-[Co II (te2f2p)] 2- solution, the complex is indeed paramagnetic with an effective magnetic moment µeff = 4.9(2) µB (units of Bohr magneton). Comparing with the spin-only magnetic moment µspin-only = ge[S(S + 1)] ½ µB = 3.88 µB, it is clear that the orbital contribution due to the spin-orbit coupling is important in this complex. The measured value of the effective magnetic moment confirms a high-spin d [START_REF] Nitsche | Pseudocontact shifts in biomolecular NMR using paramagnetic metal tags[END_REF] configuration, as it falls close to the common µeff range 4.8-5.2 µB. [START_REF] Holleman | Inorganic Chemistry[END_REF] Given the high magnetic moment of the central cobalt(II) ion, a strong paramagnetic broadening of the NMR signals was expected to negatively impact the spectral resolution and to leave any J-coupling pattern indistinguishable. Surprisingly, in our case, well-resolved 1 H (Figure 4) and 19 F NMR (Figure 5) spectra of trans-[Co II (te2f2a)] and trans-[Co II (te2f2p)] 2-, and a 13 C NMR spectrum of trans-[Co II (te2f2p)] 2-(Figure 6) complexes were obtained (while a 13 C NMR spectrum of trans-[Co II (te2f2a)] could not be obtained within reasonable experimental time due to low solubility of the complex). caused by the interaction of the 13 C nuclei with the paramagnetic cobalt(II). In order to get insight into this interaction and fully assign the 13 C spectrum, a combined ab-initio/DFT modelling was performed.

Previous studies have shown that theoretical predictions of pNMR shifts are very sensitive to the geometry of the metal coordination polyhedron. [START_REF] Benda | Pseudocontact NMR shifts over the paramagnetic metalloprotein CoMMP-12 from first principles[END_REF] In the case of the trans-[Co II (Hte2f2p)] - anion, the ligand in the XRD structure contains one single-protonated phosphonate group which breaks the central symmetry of the molecule including the symmetry of the cobalt(II) first coordination sphere. This protonation state is not possible in the aqueous solution at pH > 7 used in the NMR experiments, where the phosphonate groups are fully deprotonated. [START_REF] Blahut | Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for 19 F magnetic resonance imaging[END_REF]40 Therefore, after removing the phosphonate hydrogen atom from the XRD structure, the trans-[Co II (te2f2p)] 2-anion was taken as the initial model for the QC calculations and optimised on a DFT level using an implicit dielectric model of the aqueous solution. Although no symmetry restriction was applied during the calculation, the obtained structure is effectively centrosymmetric (see Table 2 for a comparison of crystallographic and DFT-based coordination distances, and Table S3 for the Cartesian coordinates of the calculated structure).

* It should be noted that this signal with such an extreme 13 C shift was not originally observed.

It was looked for and detected with an adjusted pulse offset only after the QC calculations gave an indication that the carbon atom of the -CF3 group is exposed to such a strong paramagnetic shift. 2). b Structure optimised on the PBE0-D3BJ level with an implicit model of aqueous solution.

The isotropic NMR shifts were calculated using recent reformulation of Kurland and McGarvey theory established by Vaara. [START_REF] Vaara | Magnetic couplings in the chemical shift of paramagnetic NMR[END_REF][START_REF] Kurland | Isotropic NMR shifts in transition metal complexes: The calculation of the Fermi contact and pseudocontact terms[END_REF] This formalism is generally applicable to any singlemetal centre with known g-tensor (g) and zero-field-splitting (ZFS) tensor (D, for 𝑆 ≥ 1), and with known hyperfine coupling tensor 𝐀 ! between the metal ion and the NMR-active nucleus K.

The calculated isotropic NMR shift (𝛿 ! "#$" ) is obtained according to Equation (1).

𝛿 ! "#$" = 𝜎 %&' -𝜎 ! (%) + 𝛿 ! "(* + 𝛿 ! +" , (1)
where the terms 𝜎 %&' and 𝜎 ! (%) are the nuclear shielding of a NMR reference compound and the orbital shielding of a nucleus K, respectively. The contact and pseudo-contact shift terms 𝛿 ! "(* and 𝛿 ! +" correspond to the Fermi contact (FC) and electron-nucleus spin-dipolar (SD) hyperfine interactions, respectively. In this study, experimental chemical shifts of the analogous diamagnetic trans-[Co III (te2f2p)] -complex (𝛿 ! ,-#.#/ ) were used in place of the diamagnetic terms (𝜎 %&' -𝜎 ! (%) ) to calculate the paramagnetic shifts in trans-[Co II (te2f2p)] 2-according to Equation (1). The hyperfine shift terms are obtained by Equations ( 2) and (3). (2)

𝛿 ! +" = 0 1 ℏ3 4 5 1 6 7 8 Tr5𝐠 • 〈𝐒𝐒〉 • 𝐀 ! ;< 6 (3)
The 𝐴 ! 9: is the hyperfine coupling constant of the nucleus K and 𝐀 ! ;< is the second-rank spindipolar term of the total hyperfine coupling tensor 𝐀 ! of nucleus K. T is the thermodynamic temperature (298 K in this study), ℏ, 𝛾 ! , 𝑘 = and 𝜇 = are reduced Planck constant, gyromagnetic ratio of the nucleus K, Boltzmann constant and Bohr magneton, respectively. "Tr" indicates trace of a matrix. The 〈𝐒𝐒〉 is spin dyadic and it can be understood as a generalized 〈𝑺 < > 〉 observable in the presence of the zero-field-splitting with contribution from all ZFS levels weighted by their thermal population and including magnetic couplings among them. [START_REF] Vaara | Magnetic couplings in the chemical shift of paramagnetic NMR[END_REF] It should be mentioned that the pseudo-contact shift of Equation ( 3), rooted in quantum chemistry, is subject to an ongoing debate since a conflicting expression has been known within the framework of traditional semiempirical theory. [START_REF] Kurland | Isotropic NMR shifts in transition metal complexes: The calculation of the Fermi contact and pseudocontact terms[END_REF][START_REF] Parigi | Pseudocontact shifts and paramagnetic susceptibility in semiempirical and quantum chemistry theories[END_REF] Here we just note that, in case of shifts dominated by the contact interaction, the difference between these two frameworks is small.

The g-tensor g, and the ZFS tensor D used for the calculation of the cobalt(II) spin dyadic (according Ref. 33) were obtained on a correlated multi-reference ab-initio level (see Methods) known to provide reliable results for Co(II) high-spin complexes. [START_REF] Benda | Pseudocontact NMR shifts over the paramagnetic metalloprotein CoMMP-12 from first principles[END_REF] Due to modest computational demands, the method could be applied to the whole complex studied without truncation. An accurate calculation of the ligand hyperfine coupling tensors 𝐀 ! is currently the main limitation of paramagnetic NMR shift calculation for 3d-metal ions. Hybrid DFT methods are currently best suited for calculating hyperfine couplings in systems of a relevant size; however, the amount Hartree-Fock exchange (HFX) admixture in the hybrid DFT functional is not universally transferable between systems [START_REF] Munzarová | A critical validation of density functional and coupled-cluster approaches for the calculation of EPR hyperfine coupling constants in transition metal complexes[END_REF] and, due to the absence of a benchmark ab initio computational level for hyperfine coupling, any single hybrid DFT method cannot be fully relied upon. In this study, we used for hyperfine coupling calculation the hybrid PBE functional with a HFX admixture ranging from 10% to 40% to estimate the uncertainty intervals of paramagnetic NMR shifts in trans-[Co II (te2f2p)] 2-(Table S4). For the 13 C atoms, this interval ranges from 1% to 8% of the experimental spectral width. An exception is the extremely shifted atom C9 (for carbon atom numbering, see Scheme 1) where the interval ranges over 500 ppm, i.e. 30% of the experimental spectral width By comparing the calculated and experimental isotropic 13 C NMR shifts in trans- 7 and Table 3), it was possible unambiguously assign the -CF3 carbon atom C9 (δ exp = 936 ppm). This assignment is in agreement with the observed quartet due to the (phosphonate-containing pendant), and C6 (ring propylene) but the assignment is only tentative.

[Co II (te2f2p)] 2-(Figure
The overall agreement of the calculated NMR shifts with the experimental values is good with the best matching of 𝛿 ! "#$" obtained with 30% HFX admixture in the DFT hyperfine coupling calculation. The large C9 paramagnetic shift and the possibility to measure the 1 JCF coupling in both paramagnetic trans-[Co II (te2f2p)] 2-( 1 JCF = 268 Hz) and diamagnetic trans-[Co III (te2f2p)] -( 1 JCF = 282 Hz) variants of the complex suggest an intriguing question of whether the 1 JCF coupling difference between the paramagnetic and diamagnetic forms, DJ = 1 JCF para -1 JCF dia = -14 Hz, could be ascribed to paramagnetic enhancement. Applying the recent theory of paramagnetically enhanced J-coupling, [START_REF] Cherry | Paramagnetic enhancement of nuclear spin-spin coupling[END_REF] we found that the 1 JCF paramagnetic enhancement is too small, on the order of -0.25 Hz. The observed 1 JCF coupling difference thus has a different cause, likely structural, related to the difference in charge of the central ion.

The NMR shifts were calculated for the 1 H and 19 F nuclei of trans-[Co II (te2f2p)] 2-as well. On the one hand, the broad interval of predicted 1 H NMR shifts (see Table S4) in combination with narrower spectral window (270 ppm for 1 H compared to 1800 ppm for 13 C), prevent a reliable assignment of the 1 H NMR spectrum (Figure S3). On the other hand, the calculated 19 F chemical shift agrees well with its experimental value (Tables 3 andS4). Best agreement was again obtained with 30% of HFX admixture in the DFT hyperfine coupling calculation.

Individual contributions according to Equation (1) to the calculated NMR shifts in trans-[Co II (te2f2p)] 2-are plotted in Figure 8 and listed in Table S4. Paramagnetic shifts are dominated by the Fermi contact contribution for all 13 C nuclei. With the exception of C10, the pseudocontact shift is negligible. For the 19 F NMR shift, all contributions are significant and the Fermi contact term is the largest, despite a four-bond separation between the cobalt(II) and the fluorine atom. Compared to the very large 13 C contact shift of the -CF3 group (C9, 871 ppm), the rotationally averaged -CF3 fluorine contact shift is surprisingly small (46 ppm). This illustrates how indispensable quantum chemistry calculations are for reliable interpretation of paramagnetic NMR spectra. S4.

The Fermi contact shift is linearly proportional to the contact spin density at the position of the observed nucleus and it directly reflects the spin delocalisation and spin polarisation effects. [START_REF] Bertini | The hyperfine shift[END_REF][START_REF] Autschbach | Annual Reports in Computational Chemistry[END_REF] Therefore, the NMR shifts of trans-[Co(te2f2p)] 2-anion can be rationalized by analysis of the unpaired electron density distribution. By far the most of the spin density is localized on the cobalt(II) ion, and only a small fraction is distributed to other atoms (Figure 9) through frontier molecular orbitals with a high contribution of Co(II) 3d shells (Figure 10). Nevertheless, when located at the position of NMR active nuclei, even these small fractions of spin density cause large NMR shifts. S3) which enables efficient overlap of the involved atomic orbitals. A comparable dihedral angle dependence of hyperfine couplings, similar to the Karplus curve for vicinal J-interaction in NMR spectroscopy, has indeed been reported for several systems, [START_REF] Aszalontai | Solid-state NMR study of paramagnetic bis(alaninato-κ 2 N,O)copper(II) and bis(1-amino(cyclo)alkane-1-carboxylatoκ 2 N,O)copper(II) complexes: Reflection of stereoisomerism and molecular mobility in 13 C and 2 H fast magic angle spinning spectra[END_REF] supporting our present interpretation.

F NMR relaxometric properties

The precise knowledge of three-dimensional and electronic structure of the complexes studied allows us to analyse their nuclear relaxation properties which are of fundamental importance for application in 19 F MRI. Paramagnetic relaxation enhancement and the associated 19 3 Hz (small enough to show the J-coupling with protons of the neighbouring methylene group), the Co(II) ion induces a ten-fold larger linewidth of approx. 30 Hz at 7.0 T external field. An even stronger paramagnetic relaxation enhancement was observed for T1 relaxation (Table 4).

Complexes of cobalt(II) provide approximately 40-times faster 19 F longitudinal relaxation then the cobalt(III) analogues. This effect is slightly more pronounced for the trans-[Co II (te2f2p)] 2- complex than for the trans-[Co II (te2f2a)] complex. a The T2* time is not well defined for J-split NMR signals and, therefore, T2 times are listed instead.

Within Solomon-Bloembergen-Morgan theory of paramagnetically induced relaxation, the overall NMR relaxation rate of nucleus K can be decomposed into relaxation induced by dipoledipole (𝑅 7,> ! << ), contact (𝑅 7,> ! "(* ), and Curie mechanism (𝑅 7,> ! :B% ). 48 As the geometry of the complexes is known and hyperfine coupling constants were calculated to predict chemical shifts (see above), correlation times for each relaxation mechanism are the only remaining parameters in the model (see Supporting Information). The rotational correlation time can be estimated from the Stokes-Einstein law (Eq. S9) and, therefore, electronic relaxation time (𝑇 & ) of the cobalt(II) ion is the only unknown parameter. It was fitted to minimize the difference between experimental (𝑅 7,> &?+ ) and predicted (𝑅 7,> ) 19 F NMR relaxation rates. The obtained electronic relaxation time 𝑇 & as well as the nuclear relaxation rates corresponding to different mechanisms are listed in Table 5. The dominant nuclear relaxation mechanism in all cases in Table 5 is the electron-nuclear dipole-dipole relaxation. However for T2 nuclear relaxation, the contact mechanism is also important (≈16% and ≈11% of the total 𝑅 > value for the trans-[Co II (te2f2p)] 2-and trans-[Co II (te2f2a)] complex, respectively). This scalar, through-bond relaxation mechanism is commonly neglected when predicting nuclear relaxation properties of the f-metal-based 19 F MRI CAs. [START_REF] Chalmers | Design principles and theory of paramagnetic fluorinelabelled lanthanide complexes as probes for 19 F magnetic resonance: a proof-of-concept study[END_REF] However, for the MRI CAs based on d-elements, especially if the observed nucleus is just a couple of bonds away from the metal ion, the contact contribution must be taken into account as it can cause significant decrease of the MRI CA efficiency. Finally, the effect of the Curie relaxation is less important compared to the two other mechanisms. The obtained electronic relaxation times for cobalt(II) are in agreement with literature values and indicate that an Orbach mechanism is probably the dominant electronic relaxation pathway. 48 The T2*/T1 ratio is commonly used to estimate efficiency of paramagnetic molecules as MRI CAs. The ratio reflects the time required to create equilibrium magnetization relative to the time for signal detection. The T2*/T1 ratios for trans-[Co(te2f2p)] 2-and trans-[Co(te2f2a)] complexes are 0.78 and 0.68 (at 7.0 T), respectively. These values are higher (i.e. higher CA efficiency) than those previously published for nickel(II) complexes where T2 * /T1 ratios ranged from 0.32 to 0.48. [START_REF] Blahut | Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for 19 F magnetic resonance imaging[END_REF][START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF] They are, however, lower than those reported for a number of other macrocyclic complexes with f and d-transition ions, including a Dy(III) complex of a DOTA-diamide derivative with two -CF3 groups (T2 * /T1 = 0.96; 4.7 T, 295 K), [START_REF] Chalmers | Strategies to enhance signal intensity with paramagnetic fluorine-labelled lanthanide complexes as probes for 19 F magnetic resonance[END_REF] Fe II /Co II /Ni II complexes of a DOTA-tetramide derivative with six -CF3 groups (T2 * /T1 ~ 0.9; 9.4 T, 296 K), [START_REF] Yu | Highly fluorinated metal complexes as dual 19 F and PARACEST imaging agents[END_REF] or a Ni(II) complex of cross-bridged cyclam derivatives with one/two -CF3 groups (T2 * /T1 ~0.8; 7.1 T, 298 K). [START_REF] Pujales-Paradela | Reinforced Ni(II)-cyclam derivatives as dual 1 H/ 19 F MRI probes[END_REF] Nevertheless, the T2 * /T1 ratios of the present cobalt(II) complexes are significantly higher than those in M-DOTA-AmF12 complexes with the T2 * /T1 values 0.07-0.18 and 0.57 (7 T, 298 K) for M = Ln 3+ and Fe 2+ , respectively. [START_REF] Srivastava | Fe-and Ln-DOTAm-F12 are effective paramagnetic fluorine contrast agents for MRI in water and blood[END_REF] They are also higher or comparable with the T2 * /T1 values 0.12-0.87 (7 T, 298 K) of Ln(III) complexes of DOTA-mono/diamide derivatives with two -CF3 groups. 52 Both cobalt(II) complexes studied also show a significantly better T2 * /T1 ratio than e.g. micelles of perfluorinated molecules with dissolved paramagnetic complexes, 0.31 and 0.05 (9.4 T, 298 K) for Fe III and Gd III acetylacetonate complexes, respectively, [START_REF] Kislukhin | Paramagnetic fluorinated nanoemulsions for sensitive cellular fluorine-19 magnetic resonance imaging[END_REF]

Experimental

Commercial chemicals (Merck-Aldrich, CheMatech, Lachema) were used as obtained. The ligands, H2te2f2a and H4te2f2p, were available from our previous work. [START_REF] Blahut | Nickel(II) complexes of N-CH2CF3 cyclam derivatives as contrast agents for 19 F magnetic resonance imaging[END_REF][START_REF] Blahut | Paramagnetic 19 F relaxation enhancement in nickel(II) complexes of N-trifluoroethyl cyclam derivatives and cell labeling for 19 F MRI[END_REF] The [Co(NH3)6]Cl2 complex was prepared by the published procedure [START_REF] Kauffman | Hexaamminecobalt(II) chloride[END_REF] The effective magnetic moment (µB = 4.9(2) µB) was measured using Evans method for detection of the bulk magnetic susceptibility through a difference in chemical shift of t-BuOH between the sample at a given concentration and a reference solution in a coaxial insert tube. [START_REF] Corsi | Determination of paramagnetic lanthanide(III) concentrations from bulk magnetic susceptibility shifts in NMR spectra[END_REF] water allowing characterization only by 1 H and 19

Calculation details on the trans-[Co II (te2f2p)] 2-complex

Geometry optimisation was performed in Gaussian 09 (Revision D.01) 57 by DFT employing the hybrid PBE0 functional [START_REF] Perdew | Generalized gradient approximation made simple[END_REF][START_REF] Perdew | Rationale for mixing exact exchange with density functional approximations[END_REF] with Grimme's D3 dispersion correction using Becke-Johnson damping. [START_REF] Grimme | A consistent and accurate ab initio parameterization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu[END_REF][START_REF] Grimme | Effect of the damping function in dispersion corrected density functional theory[END_REF] The triple-zeta basis set TZVP was used for all atoms. 62 An UltraFine integration grid was applied. Bulk solvent effects of water were simulated by polarisable continuum model. [START_REF] Scalmani | Continuous surface charge polarizable continuum models of solvation. I. General formalism[END_REF] The identity of energetic minima was verified by vibrational frequency analysis.

The g-tensor and the zero-field-splitting tensor of the cobalt(II) complex were obtained in Orca 4.0 64 by the effective Hamiltonian approach applied on the wave function calculated in-vacuo using the state-averaged complete active space self-consistent field method (with seven electrons in five 3d-orbitals, i.e. SA-CASSCF (7,5), weighing equally all 10 quartet and 40 doublet roots) with the n-electron valence state perturbation theory (NEVPT2) correction. The TZVP base set was used for all the atoms. 62 The hyperfine coupling tensors for all NMR active nuclei were calculated in Orca 4.0 64 with a series of hybrid PBE functionals with Hartree-Fock exchange varying from 10 to 40 %. The IGLO-III basis set [START_REF] Kutzelnigg | NMR -Basic Principles and Progress[END_REF] was used for the NMR active atoms and Def2-TZVPD for the rest. [START_REF] Weigend | Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy[END_REF][START_REF] Rappoport | Property-optimized Gaussian basis sets for molecular response calculations[END_REF] Paramagnetic NMR shifts were calculated with the methodology of Vaara et al. [START_REF] Vaara | Magnetic couplings in the chemical shift of paramagnetic NMR[END_REF] The temperature 300 K was used in all calculations of NMR shifts. The calculated NMR shifts of symmetry-equivalent nuclei were averaged, same as were the 19 F chemical shifts of the freely rotating -CF3 group.

Analysis of relaxation times

  Scheme 1. Ligands discussed in this work.

Figure 1 .

 1 Figure 1. Molecular structure of trans-[Co II (te2f2a)] complex found in the crystal structure of

  Analogous distances found in the structure of the trans-[Co III (te2f2p)] -anion are all in the range d(P-O) = 1.510-1.511 Å, clearly pointing to a full deprotonation (Figure 3).

Figure 2 .

 2 Figure 2. Molecular structure of trans-[Co II (Hte2f2p)] -anion found in the crystal structure of

Figure 3 .

 3 Figure 3. Molecular structure of trans-[Co III (te2f2p)] -anion found in the crystal structure of

Figure 4 .Figure 5 .

 45 Figure 4. 1 H NMR (300 MHz, D2O) spectra of (A) trans-[Co II (te2f2p)] 2-(pD 10.9) and (B)

Figure 6 .

 6 Figure 6. 13 C NMR spectra of trans-[Co II (te2f2p)] 2-complex (151 MHz, D2O, pD 7.0). (A) The

1

  JCF coupling. The ethylene C3 carbon atom was assigned unambiguously as well (δ exp = -670 ppm). The signals with experimental chemical shifts δ exp = -425, -515, and -384 ppm most probably correspond to ethylene C2, and propylene C7 and C5 carbon atoms of the macrocycle, respectively. The order is not unambiguous. The remaining three resonances, δ exp = -125, -76, and -49 ppm probably correspond to carbon atoms C8 (fluorine-containing pendant), C10

Figure 7 .

 7 Figure 7. Comparison of experimental (horizontal axis) and calculated (vertical axis) 13 C NMR

Figure 8 .

 8 Figure 8. Contributions to calculated 13 C and 19 F NMR shifts in trans-[Co(te2f2p)] 2-anion: The

Figure 9 :

 9 Figure 9: Positive (green) and negative (violet) iso-surfaces of unpaired electron density in the

Figure 10

 10 Figure 10 Frontier natural orbitals in trans-[Co(te2f2p)] 2-anion corresponding to cobalt(II) 3d

  F line broadening is evident from the comparison of 19 F NMR spectra of paramagnetic trans-[Co II (te2f2a)] and trans-[Co II (te2f2p)] 2-with those of their diamagnetic Co(III) counterparts (Figure 5). While the 19 F NMR linewidth of the diamagnetic Co(III) complexes is approximately

54 Conclusion

 54 or 0.47 (9.4 T, 298 K) for a Fe III Schiff base complex.We prepared and investigated kinetically inert high-spin cobalt(II) complexes of carboxylate/phosphonate cyclam derivatives together with their cobalt(III) analogues as diamagnetic references. These complexes are examples of a growing family of paramagnetic MRI probes based on transition metal ions, and the present study demonstrates that these systems exhibit a convenient T2 * /T1 ratio which, under suitable acquisition conditions, can lead to efficient19 F MRI CA. In addition, paramagnetic chemical shifts of the trans-[Co II (te2f2p)] 2- complex were interpreted with the help of ab-initio and DFT calculations. The simulations indicate delocalisation of single-occupied molecular orbitals from cobalt(II) ion to ligand atoms, especially to the relatively distant -CF3 group. The resulting contact spin density explains an extreme 13 C NMR shift of almost 1000 ppm. The simulation also shows the importance of contact contribution to the 19 F T2 nuclear relaxation which, unlike in lanthanide(III) ion complexes, cannot be neglected in transition metal ion complexes. These calculations are among only a handful available for transition metal-based systems with macrocyclic ligands. Thus, this study may help future works with interpretation of paramagnetic NMR shifts and relaxation data of novel transition-metal MRI CAs as the area is much less developed than the analogous field of trivalent lanthanide complexes.

  Electronic relaxation time of Co(II) was calculated by minimizing the difference between experimental T1( 19 F) and T2( 19 F) relaxation times [assumed equal to T2*( 19 F)] and the values predicted from Solomon-Bloembergen-Morgan equations, see SI and Ref. 48. The diamagnetic contribution to the nuclear relaxation rate was neglected. Average metal-fluorine distances were taken from X-ray structures and hyperfine coupling constants (𝐴 ! 9: ) (0.227 MHz and 0.278 MHz for trans-[Co II (te2f2a)] and trans-[Co II (te2f2p)] 2-, respectively) from the DFT calculation using 30% Hartee-Fock exchange admixture (see above). Rotation correlation times (0.19 ns and 0.21 ns for trans-[Co II (te2f2a)] and trans-[Co II (te2f2p)] 2-, respectively) were estimated from Stokes law in water solution (Eq. S9). ASSOCIATED CONTENT Supporting Information contains: data on complexation mechanism and decomplexation kinetics; X-ray experimental data and details; Cartesian coordinates of the DFT-optimised trans-[Co II (te2f2p)] 2-structure; detailed results of the pNMR shift calculations; comparison of calculated 1 H NMR shifts with experimental 1 H NMR spectrum of trans-[Co II (te2f2p)] 2-and theory for 19 F NMR relaxation calculations. Accession Codes: CCDC 1861164-1861166 contain the supplementary crystallographic data

Table 1 .

 1 Selected geometric parameters found in crystal structures of the studied complexes.

	Parameter	trans-	(NH4){trans-	(NH4){trans-
		[Co II (te2f2a)]×2MeOH a	[Co II (Hte2f2p)]}×3.5H2O	[Co III (te2f2p)]}×11H2O a
		Bond lengths (Å)
	Co-O11A	2.054(1)	2.071(2)	1.896(1)
	Co-O11B	2.054(1)	2.106(2)	1.896(1)
	Co-N1A	2.252(1)	2.253(2)	2.125(1)
	Co-N4A	2.117(1)	2.147(2)	2.009(1)
	Co-N1B	2.252(1)	2.256(2)	2.125(1)
	Co-N4B	2.117(1)	2.129(2)	2.009(1)
	Average Co•••F	5.26	5.24	5.14
		Bond angles (°)
	O11A-Co-O11B	180	176.54(7)	180

Table 2 .

 2 Comparison of coordination distances found in the single-crystal XRD structure of

	(NH4){trans-[Co II (Hte2f2p)]}×3.5H2O and in the DFT-optimised structure of trans-
	[Co II (te2f2p)] 2-anion.
	Distance / Å	X-ray a	DFT b
	Co-O11	2.071(2)/2.106(2) 2.042
	Co-N1	2.253(2)/2.256(2) 2.281
	Co-N4	2.147(2)/2.129(2) 2.148

a Non-centrosymmetric molecule in the solid state (Figure

Table 3 .

 3 Experimental

		and predicted 13 C and 19 F NMR shifts (in ppm) in trans-[Co(te2f2p)] 2-
	anion, and the calculated Fermi contact hyperfine coupling constants (in MHz; obtained with
	30% HFX admixture in the DFT functional). For the atom numbering scheme, see Scheme 1.
	Nucleus K	𝛿 ! &?+	𝛿 ! "#$"	𝐴 ! 9:

Table S4

 S4

	C2	-425	-407	-0.703
	C3	-670	-727	-1.343
	C5	-384	-302	-0.647
	C6	-49	162	0.201
	C7	-515	-531	-0.810
	C8	-125	-263	-0.410
	C9	936	967	1.398
	C10	-76	-59	-0.534
	F	-23.0	-27 a	-0.278 a
		.

Table 4 .

 4 19 F NMR relaxation times (in ms) and shifts (in ppm) of Co II/III complexes (at 25 °C, pH ~7) measured at two different static magnetic field strengths (B0, in T).

			T1 (ms)		T2* (ms)	δF (ppm)
	Complex
		B0 7.0	9.4	7.0	9.4	7.0	9.4
	trans-[Co II (te2f2p)] 2-	12.3(2) 11.94(4)	9.6	8.9	-23.0	-22.9
	trans-[Co II (te2f2a)]	16.1(5) 15.61(5)	11.0	10.4	-25.4	-25.2
	trans-[Co III (te2f2p)] -	600(20) 500(19)	360(90) a 321(100) a -59.2	-59.2
	trans-[Co III (te2f2a)] +	660(50) 573(31)	540(130) a 460(150) a -59.4	-59.5

Table 5 .

 5 Experimental19 F NMR relax`ation rates (𝑅 7,> &?+ ) and the decomposition of the predicted

	19 F NMR relaxation rates (𝑅 7,> "#$" ) into relaxation induced by dipole-dipole (𝑅 7,> << ), contact (𝑅 7,> "(* ),
	and Curie (𝑅 7,> :B% ) mechanism, based on the fitted electronic relaxation time (𝑇 Parameter trans-[Co II (te2f2p)] 2-trans-[Co II (te2f2a)]
		𝐵 C 7.0	9.4	7.0	9.4
	𝑅 7 &?+	81.3	83.8	62.1	64.1
	𝑅 7	78.0	81.8	67.7	69.5
	𝑅 7 <<	73.3	75.3	63.1	63.6
	𝑅 7 "(*	1.1	0.6	0.9	0.5
	𝑅 7 :B%	3.6	5.9	3.3	5.5
	𝑅 > &?+	104.0	112.0	90.9	96.2
	𝑅 >	106.2	113.3	86.3	90.9
	𝑅 > <<	84.2	87.1	72.2	73.4
	𝑅 > "(*	17.4	18.3	10.0	10.3
	𝑅 > :B%	4.6	7.9	4.1	7.1

& , in ps). The relaxation rates (all in s -1 ) were measured and calculated at two different static magnetic field strengths (𝐵 C , in T).

  and stored in flame-sealed Ar-flushed ampoule (as a solid) or dissolved in ≈10% oxygen-free aq. NH3 (to get a stock solution for the title complex syntheses). The NMR spectra were recorded employing VNMRS300, VarianUNITY INOVA 400, Bruker Avance III 400, and Bruker Avance III 600 spectrometers using 5-mm sample tubes. NMR chemical shifts are given in ppm and coupling constants are reported in Hz. Unless stated otherwise, all NMR spectra were collected at 25 °C. For the 1 H and used. ESI-MS spectra in positive or negative mode were acquired on the Bruker ESQUIRE 3000 spectrometer with ion-trap detection. High-resolution mass spectra were recorded on Orbitrap XL (Thermo Fisher Scientific).

	(NH4){trans-[Co II (Hte2f2p)]}
	Under argon, H4te2f2p (200 mg, 360 μmol), was dissolved in oxygen-free aq. NH3 (5%, 20
	mL) and [Co(NH3)6]Cl2 stock solution in ≈10% oxygen-free aq. NH3 (86 mM, 10 mL, i.e. 860
	μmol, 2.4 equiv.) was added. The reaction proceeded under reflux and under a flow of oxygen-
	free ammonia overnight. Presence of the free ligand was tested using 19 F NMR. On air, the
	reaction mixture was evaporated to dryness and the crude product was purified by column
	chromatography (SiO2, 6×3 cm) with EtOH / conc. aq. NH3 = 5 : 1 as a mobile phase. Fractions
	containing pure product were combined (visually detectable by a pink colour), solvents were
	evaporated to dryness and the solid residue was recrystallized from a minimal amount of water
	13 C NMR measurements in D2O, t-BuOH was used as internal standard (δ( 1 H) = 1.25 ppm,
	with a drop of 5 % aq. NH3 by vapor diffusion of acetone. Yield 174 mg (79 %). For 1 H, 19 F and
	δ( 13 C) = 30.29 ppm). pD values were calculated adding +0.4 as a correction to pH reading using
	13 C NMR, see Figures 4, 5 and 6, respectively. HR-MS(-): 608.0803; calc. for {[Co(te2f2p)] 2-+
	a combined glass electrode calibrated with commercial buffer solutions in H2O. For 19 F NMR
	H + } -: 608.0804. TLC (SiO2; EtOH / conc. aq. NH3 = 1/5): RF 0.6. 1 H (300 MHz, D2O, pD 10.9):
	measurements, 2,2,2-trifluoroethanol (TFE, δ( 19 F) = -77.0 ppm) was used as internal standard.
	182 (bs); 173 (bs); 115 (bs); 82 (bs); 71 (bs); 39 (bs); 34 (bs); 33 (bs); 18 (bs); -1 (bs); -80 (bs);
	Abbreviations s (singlet), t (triplet), q (quartet), m (multiplet) and b (broad) are used in order to
	-82 (bs); -104 (bs); 13 C (151 MHz, D2O, pD 7): 936 (q, 1 JCF = 268 Hz, C9); -49(s, C6); -76 (s,
	express the signal multiplicities/shape. Symbol α and β indicate resolved but not assigned (axial
	C10); -125 (s, C8); -384 (s, C5); -425 (s, C2); -515 (s, C7); -670 (s, C3). 19 F (282 MHz, D2O,
	vs. equatorial) geminal protons of CH2 groups. Longitudinal relaxation times T1 were measured
	pH ~7): -23.0;
	using an inversion recovery sequence. Transversal relaxation times were measured using a
	CPMG pulse sequence. Relaxation times T2* were calculated from signal half-width 𝜈½ using the

relation T2* = 1/(π 𝜈½). The concentration of the complexes for spectral measurements was ~10 mg per 0.5 mL of solvent. In case of trans-[Co II (te2f2a)], a saturated solution of the complex in water was

  75%, 18 mg, ≈78 μmol, ≈4 equiv.) was added. The reaction was left to proceed for 10 min and excess of benzoic acid derivatives was filtered off. Prepared cobalt(III) complex was studied only in solution without isolation. NMR data: 1 H (600 MHz, D2O, pD 6.9): 2.16 (dt, Single crystals of trans-[Co II (te2f2a)]×2MeOH were grown by cooling of saturated hot solution of trans-[Co II (te2f2a)] in methanol. Single crystals of (NH4){trans-[Co II (Hte2f2p)]}×3.5H2O and (NH4){trans-[Co III (te2f2p)]}×11H2O were prepared by vapor diffusion of acetone into solution of the corresponding complex in water with a small amount of ammonia. Other details on refinement of X-ray data and final experimental data (TableS2) are given in Supporting Information. Complete crystallographic records for the three structures have been deposited in the Cambridge Crystallographic Data Centre under CCDC reference numbers 1861164-1861166.

	F NMR (Figures 5 and 6, respectively). HR-
	MS(+): 538.1417 (calc. for {[Co(te2f2a)] + H + } + 538.1420), 560.1235 (calc. for {[Co(te2f2a)] +
	Na + } + 560.1239). 1 H (300 MHz, D2O, pD 9.1): 246 (bs); 204 (bs); 151 (bs); 86 (bs); 96 (bs) 70
	(bs); 60 (bs); 58 (bs); 55 (bs); -33 (bs); -64 (bs); -88 (bs); -92 (bs); -129 (bs); 19 F (282 MHz,
	D2O, pH ~7): -25.4.
	Solution of trans-[Co III (te2f2a)] +
	The complex trans-[Co II (te2f2a)] (10 mg, 19 μmol) was suspended in D2O (0.7 mL, pD 9.2)
	containing conc. aq. NH3 (10 μL). The oxidant, solid m-chloroperoxybenzoic acid (MCPBA,
	assayed as 70-

JHH = 14.3,

JHH = 2.8 Hz, 2H, H7α); 2.29 (dt, 2 JHH = 17.3, 3 JHH = 2.3 Hz, 2H, H6α); 2.50 (m,

www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Schaefer, A.; Huber, C.; Ahlrichs, R. Fully optimized contracted Gaussian-basis sets of triple zeta valence quality for atoms Li to Kr. J. Chem. Phys. 1994, 100, 5829-35.

Paramagnetically induced NMR shifts and relaxations of cobalt(II) complexes with trifluoroethyl cyclam derivatives were interpreted on the basis of electron spin density calculations, and the complexes are suggested as19 F MRI contrast agents.

Funding Sources

The Ministry of Education of the Czech Republic (Grant LTC 17067).

The ELIXIR-CZ project (LM2015047), part of the international ELIXIR infrastructure. The IT4Innovations National Supercomputing Center (LM2015070).

ACKNOWLEDGMENT

This study was funded by the Ministry of Education of the Czech Republic (Grant LTC 17067).

Computational resources were provided by the project e-Infrastruktura CZ (LM2018140) and IT4Innovations National Supercomputing Center (LM2015070). The authors thank Dr. I.

Císařová for X-ray data acquisition. The work was performed in the framework of the EU COST CA15209 Action.

Solution of trans-[Co III (te2f2p)] -

Complex (NH4)[Co II (Hte2f2p)] (8 mg, 13 μmol) was dissolved in D2O (0.7 mL, pD 10.9) containing conc. aq. NH3 (10 μL). The oxidant, solid m-chloroperoxybenzoic acid (MCPBA, assayed as 70-75%, 13 mg, ≈53 μmol, ≈4 equiv.) was added. The reaction was left to proceed for 10 min and excess of the benzoic acid derivatives was filtered off. The NMR experiments were performed directly with this sample. NMR data: 1 H (600 MHz, D2O, pD 6.9): 1.52 ( Hz, 2H, H8β); 3.66 (t, 2 JHH = 15 Hz, 2H, H10β); 3.72 (t, 2 JHH = 3 JHH = 13 Hz, 2H, H5α); 3.86 (t, 2 JHH= 3 JHH = 14 Hz, 2H, H3α); 4.36 (t, 2 JHH = 3 JHH= 14 Hz, 2H, H2α); 13 C{ 1 H} (151 MHz, D2O, pD 6.9): 23.6(s, C6); 52.2 (q, 2 JCF = 29 Hz, C8); 52.7(s, C7); 56.3(s, C2); 57.1 (d, 1 JPC = 131 Hz, C10); 60.7 (d, 3 JPC = 9.4 Hz, C5); 68.5(s, C3); 122 (q, 1 JCF = 285 Hz, C9); 19 F (282 MHz, D2O, pD 6.9): -59.22 (t, 3 JHF = 9.4 Hz); 31 P (121 MHz, D2O, pD 6.9): 38.25.

trans-[Co II (te2f2a)]

Under argon, H2te2f2a (100 mg, 420 μmol) was dissolved in oxygen-free solution of [Co(NH3)6]Cl2 (60 mM) in ≈10% aq. NH3 (10 mL, i.e. 600 μmol, 1.4 equiv.). The reaction mixture was refluxed under gentle flow of oxygen-free ammonia. The resulting trans-[Co II (te2f2a)] precipitated from the reaction mixture in a form of small crystals during the reaction course. The solid product was filtered off after disappearance of the free ligand signal in 19 F NMR of reaction solution (~14 h). Yield 60 mg (60 %). The complex is hardly soluble in

AUTHOR INFORMATION

Corresponding Author

* petrh@natur.cuni.cz, blahutj89@gmail.com, Hlavova 2030, 12843 Prague 2, Czech Republic.

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.