Imidazole-Appended Macrocyclic Complexes of Fe(II), Co(II), and Ni(II

Mar 30, 2017 - Fe(II), Co(II), and Ni(II) complexes with imidazole pendent groups are studied as paramagnetic chemical exchange saturation transfer (p...
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Imidazole-Appended Macrocyclic Complexes of Fe(II), Co(II), and Ni(II) as ParaCEST Agents Patrick J. Burns, Jordan M. Cox, and Janet R. Morrow* Department of Chemistry, University at Buffalo, The State University of New York, Amherst, New York 14260, United States S Supporting Information *

ABSTRACT: The solution chemistry and solid state structures of the Co(II), Fe(II), and Ni(II) complexes of N,N′bis(imidazole-2-ylmethyl)-4,10-diaza-15-crown-5 (HINO) are reported. The Co(II) and Ni(II) complexes of HINO are the first examples of paraCEST agents (paramagnetic chemical exchange saturation transfer) that feature exchangeable imidazole NH protons. The crystal structures of [Co(HINO)]CoCl4·H2O and [Fe(HINO)](CF3SO3)2 have the metal ions coordinated to four nitrogen and three oxygen donor atoms of the macrocyclic ligand in a distorted pentagonal bipyramidal geometry. In [Ni(HINO)](CF3SO3)2, the nickel ion is bound to only two of the three ether oxygens and three nitrogens to produce a complex with a distorted octahedral geometry. The 1 H NMR spectra of the three paramagnetic complexes show resonances characteristic of effective C2 symmetry in solution. CEST peaks attributed to the imidazole NH proton of the pendent group are observed at 32 and 55 ppm away from bulk water for [Co(HINO)]2+ and [Ni(HINO)]2+, respectively, on a 11.7 or 9.4 T NMR spectrometer. For both complexes, an optimal CEST effect was observed at pH 7.2, and the rate constant for proton exchange under these conditions was 1.0 × 103 s−1. [Fe(HINO)]2+ did not produce a CEST peak due to oxidation of the complex in water at neutral pH. The CEST peak of [Co(HINO)]2+ or [Ni(HINO)]2+ is observed in the presence of human serum albumin (HSA). These complexes show enhanced kinetic inertness toward dissociation in acid or in the presence of HSA in comparison to analogous complexes with amide pendent groups.

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INTRODUCTION The development of MRI contrast agents that contain transition metal ions creates opportunities for chemists to design new ligands and to study the coordination chemistry of these complexes. Transition metal ion complexes are under investigation for the development of MRI contrast agents known as paramagnetic chemical exchange saturation transfer (paraCEST) agents.1−6 ParaCEST agents contain metal ions that produce large paramagnetic induced proton chemical shifts without unduly broadening resonances.7,8 Our laboratory2−5,9−11 and others12 have developed transition metal paraCEST agents based on Fe(II), Co(II), and Ni(II). Recently, analogous transition metal ion complexes that are used in magnetic resonance spectroscopy as paraSHIFT (paramagnetic shift) agents13 have also been reported.14,15 Macrocyclic ligands are typically used for Fe(II), Co(II), or Ni(II) paraCEST or paraSHIFT agents in order to produce complexes that are kinetically inert to dissociation and are thermodynamically stable.1,16 In many cases it is advantageous to encapsulate the metal ion to insulate it from other biologically relevant small molecule ligands and proteins. Our work has shown that macrocycles that form six-,2−5,10 seven-,10,17 or eight-coordinate9,10 complexes are suitable for Fe(II), Co(II), or Ni(II) paraCEST agents. The macrocycle © 2017 American Chemical Society

must also contain donor groups with protons that chemically exchange with water. Generally, these exchangeable protons derive from pendent groups on the macrocycle backbone. One macrocycle backbone of particular usefulness for testing new donor groups is the 4,10-diaza-15-crown-5 macrocycle.17 Derivatives of this macrocycle form rigid complexes with Fe(II), Co(II), or Ni(II) that produce sharp paramagnetically shifted 1H NMR spectra. Previous research in our group on the macrocycle, CYNO in Scheme 1, showed that the amide groups produced highly shifted and sharp CEST peaks.17 Heterocyclic groups with exchangeable NH protons have been used in the development of paraCEST agents based on transition metal ions5,11,14 and, to a more limited extent, for lanthanide ion paraCEST agents.18 Recently, 2-amino-6-picolyl donor groups have been reported for Fe(II), Co(II), and Ln(III) complexes, but so far these groups have suboptimal CEST effects such as being only moderately shifted, highly broadened, or, for Ln(III) complexes, not readily detectable.11,18 Pyrazole pendent groups have been successfully used for paraCEST agents.5,12 For example, a Co(II) complex with pyrazole pendent groups has been reported as an oxygen Received: January 19, 2017 Published: March 30, 2017 4545

DOI: 10.1021/acs.inorgchem.7b00176 Inorg. Chem. 2017, 56, 4545−4554

Article

Inorganic Chemistry

minimal chloroform, and hexanes were added to the solution to produce a gray-white suspension that settled to produce a yellow oil. The suspension was allowed to settle for 5 min, and then the upper layer was decanted and the oil discarded. The solvent was removed from the solution to produce 112 mg of beige oil (yield 40%). The oil was used without further purification. ESI-MS m/z: 190.2 (M/2), 379.2 (M + H+), 401.3 (M + Na+). 1H NMR (400 MHz, CDCl3): δ = 6.91 (s, imidazole CH, 2H), 3.79 (s, alkyl CH2, 2H), 3.51 (s, ring CH2, 2H), 3.39−3.34 (m, ring CH2, 4H), 2.78−2.77 (t, ring CH2, 2H), 2.72−2.70 (t, ring CH2, 2H). 13C NMR (75 MHz, CDCl3): δ = 147.20, 69.72, 68.39, 68.35, 56.81, 56.24, 53.85. Synthesis of Complexes. [Co(HINO)]2+ was prepared by addition of CoCl2·6H2O (19 mg 0.080 mmol) to a solution of HINO (30 mg 0.079 mmol) in ethanol at room temperature for 1h. The resulting precipitate was isolated via vacuum filtration and washed with cold ethanol to produce a light blue powder (14.2 mg, 35% yield). ESI-MS m/z, relative intensity, %: 218.8 [M − 2Cl−]2+/2 (100%), 436.2 [M − H+ − 2Cl−]+ (47.2%). Likewise, the nitrate salt was prepared by adding Co(NO3)2·6H2O to a solution of HINO in acetonitrile. The resulting purple solution was then stirred for an hour before addition of diethyl ether, producing a pink solid. ESI-MS m/z, relative intensity in %: 218.8 [M − 2NO3−]+/2 (100%), 436.2 [M − H+ − 2NO3−]+ (20.3%). [Ni(HINO)]2+ was prepared by stirring Ni(CF3SO3)2 (140 mg, 3.92 mmol) in equimolar ratio with HINO (149 mg, 3.94 mmol) in acetonitrile, with gentle heating of the solution. After 1 day, the solution was allowed to cool and a precipitate formed. The solid was removed by filtration, and the solution was placed on a rotary evaporator. A green oil was produced upon removal of solvent. The resulting oil was dissolved in minimal ethanol (1−2 mL), and hexane was then added (10−15 mL) to the vial to precipitate green crystals of [Ni(HINO)](CF3SO3)2 (50 mg, 17% yield). ESI-MS m/z, relative intensity, %: 218.4 [M − 2CF3SO3−]2+/2 (100%), 584.9 [M − CF3SO3−]+ (71.9%), 435.2 [M − H+ − 2CF3SO3−]+ (27.6%). Fe(CF3SO3)2 (47 mg, 1.3 mmol) and HINO (50 mg, 1.3 mmol) were added to a 2-neck round-bottom flask purged with argon. Acetonitrile was added by syringe to the flask, and the reaction was stirred at room temperature for 2 h. The solvent was removed from the solution to produce an oil. The oil was redissolved in minimal ethanol, and hexanes were added to produce crystals for Xray diffraction studies (10 mg, 11% yield). ESI-MS m/z, relative intensity, %: 217.4 [M − 2CF3SO3−]2+/2 (100%), 582.9 [M − CF3SO3−]+ (32.8%), 433.2 [M − H+ − 2CF3SO3−]+ (32.6%). Alternatively, the chloride salt was prepared by stirring FeCl2·4H2O (27 mg, 1.4 mmol) in ethanol with equimolar ligand (52 mg, 1.4 mmol) in a flask to produce a yellow solid which was collected by vacuum filtration (19 mg, 28% yield). ESI-MS m/z, relative intensity, %: 217.3 [M − 2Cl−]2+/2 (100%), 433.2 [M − H+ − 2Cl−]+ (82.3%), 434.2 [M − H+− 2Cl−]2+ (17.9%). Determination of Magnetic Moment. The effective magnetic moment (μeff) was determined by using the Evans method.21 Samples contained 5−10 mM complex and 5% t-butanol by volume in D2O in an insert, while the outer NMR tube contained 5% by volume tbutanol in D2O. Evans measurements of magnetic susceptibility were acquired at 298 K (T). See Supporting Information (equation S1). Solution concentrations were calibrated by NMR spectroscopy by integration of resonances relative to 3-(trimethylsilyl)-1-propanesulfonic acid sodium salt as standard. CEST Experiments. CEST data were acquired on a Varian 500 or 400 MHz NMR spectrometer with a presaturation pulse power (B1) of 1000 Hz (24 μT) applied for 4 s at 37 °C. Solutions contained 8 mM complex, 100 mM NaCl, and 20 mM buffer at pH values between 6.8 and 7.8. Data were acquired in 1 ppm increments and plotted as normalized water signal intensity (Mz/M0 %) against frequency offset (ppm) to generate CEST spectra. Samples containing rabbit serum had 8 mM complex. Samples containing human serum albumin (HSA) had 4 mM complex, 100 mM NaCl, 20 mM 4-(2-hydroxyethyl)-1piperazineethanesulfonic acid (HEPES) buffer, and 35 mg/mL HSA. Exchange rate constants (kex) were calculated by using the Omega plot method as described in the Supporting Information.

Scheme 1

sensitive switch.5 The pyrazole protons are highly paramagnetically shifted by the Co(II) center and produce a CEST peak at 135 ppm.5 A pyrazole pendent group on an Fe(II) paraCEST agent has also been reported.12 One drawback of the pyrazole pendent group on the Co(II) complex is that optimal CEST is observed at slightly acidic pH values rather than at biological pH values of 7.2−7.4. For protons to give rise to a CEST effect on these relatively rapidly exchanging systems, the separation between the exchangeable proton resonance and the bulk water (Δω) must be sufficiently large to satisfy the requirement that Δω ≥ kex.19 Imidazole is another heterocyclic donor group that might provide favorable properties for paraCEST agents. Recently, imidazole derivatives have been studied as diaCEST agents by functionalizing the imidazole to modulate the rate constant for proton exchange.20 Earlier work showed that an Fe(II) complex with three benzimidazole pendent groups produced a CEST effect, but the complex is not very water-soluble. 14 Furthermore, the CEST effect is observed only at acidic pH. Here we present the first examples, to the best of our knowledge, of paraCEST agents with imidazole donor groups that produce a CEST effect through exchange of the NH proton. The rate constants for exchange in an ideal range for paraCEST agents and the maximium CEST intensity are observed at pH 7.2, making this group promising for future development of transition metal paraCEST agents.

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EXPERIMENTAL SECTION

General Instrumentation. Evans’ measurements of magnetic susceptibility, CEST data, and 1H NMR spectra were acquired on a Varian Inova 500 or 400 MHz spectrometer. Thermo Finnigan LCQ Advantage Ion Trap LC/MS equipped with a Surveyor HPLC system was used to collect mass spectral data. All pH measurements were obtained by using an Orion 8115BNUWP Ross Ultra Semi Micro pH electrode connected to a 702 SM Titrino pH meter. Synthesis of Macrocycle. HINO was prepared by the following procedure. 4,10-Diaza-15-crown-5 (161 mg, 0.74 mmol) was dissolved in 1,2 dichloroethane (50 mL) in a 3-neck round-bottom flask under argon gas. Imidazole-2-carboxaldehyde (2.7 equiv, 191 mg, 2.0 mmol) was added. The resulting suspension was stirred for an hour before addition of 3.6 equiv (564 mg, 2.7 mmol) of sodium tri(acetoxy)borohydride to the solution in dicholoroethane. Glacial acetic acid (3 drops) was added to the solution and the solution stirred under an atmosphere of argon gas. The reaction was monitored by using mass spectrometry until HINO was the major product, typically over the course of 4−7 days. The reaction was quenched using saturated sodium bicarbonate (35 mL). Afterward, the aqueous layer was collected and washed (3 × 30 mL) with chloroform. The organic layers were pooled, washed with double-distilled H2O (30 mL), and dried with anhydrous sodium sulfate. The organic layer was then dried under vacuum to produce a yellow oil. The oil was dissolved in 4546

DOI: 10.1021/acs.inorgchem.7b00176 Inorg. Chem. 2017, 56, 4545−4554

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Inorganic Chemistry Scheme 2. Synthesis of HINO

Table 1. Crystal Data, Collection, and Refinement Parameters for [Fe(HINO)](CF3SO3)2, [Co(HINO)](CoCl4)·H2O, and [Ni(HINO)](CF3SO3)2 empirical formula fw cryst syst space group cryst size (mm3) temp (K) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z ρcalc (g cm−3) μ (mm−1) F000 R1_obs R1_all wR2_obs wR2_all GOF

[Fe(HINO)](CF3SO3)2

[Co(HINO)](CoCl4)·H2O

[Ni(HINO)](CF3SO3)2

C20H30N6O9F6S2Fe 732.47 monoclinic P21/n 0.08 × 0.06 × 0.005 90 20.367(2) 13.5047(15) 22.276(2) 90 111.329(3) 90 5707.5(11) 8 1.705 0.774 3008.0 0.0496 0.0857 0.1043 0.1154 1.048

C18H32N6O4Cl4Co2 656.15 monoclinic P21 0.18 × 0.1 × 0.06 90 8.6486(3) 12.8515(5) 11.9232(5) 90 91.1061(8) 90 1324.99(9) 2 1.645 1.692 672.0 0.0212 0.0222 0.0524 0.0529 1.030

C20H30N6O9F6S2Ni 735.33 monoclinic P21/n 0.08 × 0.06 × 0.01 90 20.3644(9) 13.3889(6) 22.2130(9) 90 110.9092(12) 90 5657.7(4) 8 1.727 0.934 3024.0 0.0415 0.0673 0.0851 0.0942 1.050

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Solution Chemistry Studies. NMR samples of complex (10 mM) were incubated with 100 mM NaCl and 5 mM 3-(trimethylsilyl)-1propanesulfonic acid sodium salt as a standard. For experiments done under acidic conditions, the pD was adjusted to between 3.5 and 4.0. To study inertness to transmetalation, solutions were tested with 10 mM ZnCl2 at pD 6.5−7.0. For studies with competing anions, 25 mM K2CO3 and 0.40 mM K2HPO4 were studied between pD 7.0 and 7.5. All samples were incubated at 37 °C over a 12 h period, and determination of dissociation was done by measuring the relative intensities of paramagnetic peaks to the diamagnetic standard. X-ray Diffraction Studies. Single crystals of [Fe(HINO)](CF3SO3)2 and [Ni(HINO)](CF3SO3)2 obtained by liquid/liquid diffusion of hexanes into ethanol, and single crystals of [Co(HINO)](CoCl4)·H2O, were obtained by the slow evaporation of methanol. Suitable crystals were selected and mounted on glass fibers with oil on a Bruker SMART APEX2 CCD diffractometer installed at a rotating anode source (Mo Kα radiation, λ = 0.71073 Å). The crystals were kept at 90(2) K during data collection using an Oxford Cryosystems Cryostream 700 nitrogen gas-flow apparatus. Data for [Fe(HINO)](CF3SO3)2, [Co(HINO)](CoCl4)·H2O, and [Ni(HINO)](CF3SO3)2 were collected by the rotation method with 0.5° frame-width (ω scan) and 120, 2, and 60 s exposure times per frame, respectively. Three sets of data (360 frames in each set) were collected for [Fe(L)](CF3SO3)2 and [Ni(L)](CF3SO3)2·H2O, and five sets for [Co(L)]Cl2·2H2O, nominally covering complete reciprocal space. The structures were solved with the olex2.solve structure solution program using the Charge Flipping method and refined with the ShelXL refinement package using least squares minimization.22,23 The structures were refined by full-matrix least-squares against F2.

RESULTS The HINO ligand was prepared from reductive amination of the diazacrown ether with imidazole-2-carboxaldehyde (Scheme 2). This method was modified from a literature procedure to produce ligands via reductive amination.24 A similar approach has recently been reported.25 This type of procedure facilitated the addition of imidazole pendent groups in an unprotected form, although reaction times were lengthy and ran over the course of several days. The metal complexes were isolated following addition of the HINO macrocycle to either triflate, chloride, or nitrate salts of Fe(II), Co(II), or Ni(II). Co(II) complexes prepared with chloride or nitrate salts were used for crystallography or CEST studies, respectively. Notably, the Co(II) complex prepared from the chloride salt crystallized with CoCl42− as a counterion. In order to avoid the potentially complicating effects of a second paramagnetic center on the CEST and magnetic susceptibility measurements, the complex was also prepared and studied with nitrate as the counterion. Crystal Structures. The X-ray diffraction data for the Fe(II), Co(II), and Ni(II) complexes of HINO are summarized in Tables 1 and 2, and the complex cations are shown in Figures 1 and 2. Both [Fe(HINO)](CF3SO3)2 and [Ni(HINO)](CF3SO3)2 crystallize in a the centrosymmetric space group P21/n. Thus, there is an enantiomeric pair for each chiral complex. In addition, there are two crystallographically independent complexes in the asymmetric unit that have similar structures. An overlay of these two structures is given in 4547

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Inorganic Chemistry

Table 2. Selected Bond Lengths (Å) and Bond Angles (deg) for [Fe(HINO)](CF3SO3)2, [Co(HINO)](CoCl4)·H2O, and [Ni(HINO)](CF3SO3)2 [Fe(HINO)](CF3SO3)2

[Co(HINO)](CoCl4)·H2O

[Ni(HINO)](CF3SO3)2

Bond Lengths Fe1−O1 Fe1−O2 Fe1−O3 Fe1−N1 Fe1−N2 Fe1−N3 Fe1−N5

2.264(2) 2.321(2) 2.181(2) 2.308(3) 2.321(3) 2.096(3) 2.120(3)

Co1−O1 Co1−O2 Co1−O3 Co1−N1 Co1−N2 Co1−N4 Co1−N6

2.2154(14) 2.2976(13) 2.2388(13) 2.2864(15) 2.3166(16) 2.0658(15) 2.0713(16)

Ni1−O2 Ni1−O3 Ni1−N1 Ni1−N2 Ni1−N3 Ni1−N5

2.347(2) 2.078(2) 2.273(2) 2.160(2) 2.029(2) 2.009(2)

O1−Fe1−O2 O1−Fe1−N1 O1−Fe1−N2 O3−Fe1−O1 O3−Fe1−O2 O3−Fe1−N1 O3−Fe1−N2 N1−Fe1−O2 N1−Fe1−N2 N2−Fe1−O2 N3−Fe1−O1 N3−Fe1−O2 N3−Fe1−O3 N3−Fe1−N1 N3−Fe1−N2 N3−Fe1−N5 N5−Fe1−O1 N5−Fe1−O2 N5−Fe1−O3 N5−Fe1−N1 N5−Fe1−N2

70.86(8) 73.85(9) 141.12(9) 144.91(9) 144.16(9) 72.89(9) 70.78(9) 141.30(9) 143.66(10) 74.57(9) 90.85(10) 86.83(10) 93.13(10) 78.26(10) 104.58(11) 175.14(11) 84.74(10) 89.80(10) 91.65(10) 102.38(11) 77.82(10)

Bond Angles O1−Co1−O2 O1−Co1−O3 O1−Co1−N1 O1−Co1−N2 O2−Co1−N2 O3−Co1−O2 O3−Co1−N1 O3−Co1−N2 N1−Co1−O2 N1−Co1−N2 N4−Co1−O1 N4−Co1−O2 N4−Co1−O3 N4−Co1−N1 N4−Co1−N2 N4−Co1−N6 N6−Co1−O1 N6−Co1−O2 N6−Co1−O3 N6−Co1−N1 N6−Co1−N2

143.62(5) 145.12(5) 72.20(5) 70.09(5) 74.63(5) 71.25(5) 74.53(5) 142.54(5) 142.08(5) 142.28(5) 88.32(6) 88.24(5) 95.58(6) 79.23(6) 98.39(6) 176.40(6) 92.67(6) 88.91(6) 85.59(6) 104.37(6) 78.71(6)

O3−Ni1−O2 O3−Ni1−N1 O3−Ni1−N2 N1−Ni1−O2 N2−Ni1−O2 N2−Ni1−N1 N3−Ni1−O2 N3−Ni1−O3 N3−Ni1−N1 N3−Ni1−N2 N5−Ni1−O2 N5−Ni1−O3 N5−Ni1−N1 N5−Ni1−N2 N5−Ni1−N3

151.14(8) 73.23(8) 78.09(9) 132.93(8) 75.21(8) 151.31(9) 82.20(8) 93.00(9) 80.09(9) 102.17(9) 90.65(8) 96.36(9) 100.42(9) 82.06(9) 170.37(10)

Figure 1. Crystal structures of [Fe(HINO)](CF3SO3)2 (left) and [Co(HINO)](CoCl4)·H2O. Hydrogen atoms, solvent, and counterions omitted for clarity.

Atomic coordinates, isotropic and anisotropic displacement parameters, bond lengths, bond angles, and hydrogen atom coordinates are available in the Supporting Information (Tables S1−S18).

the Supporting Information (Figures S1 and S2). The [Co(HINO)](CoCl4)·H2O complex crystallizes in the chiral space group P21, with one metal complex, one CoCl42− counterion, and one water molecule in the asymmetric unit. 4548

DOI: 10.1021/acs.inorgchem.7b00176 Inorg. Chem. 2017, 56, 4545−4554

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Inorganic Chemistry

nitrogen atoms and to three oxygen donors of the macrocycle. The five heteroatom donors of the macrocycle are nearly planar, with root-mean-square distances of 0.216 or 0.217 Å from the plane for the [Fe(HINO)]2+ complex and 0.204 Å from the plane for the Co(II) complex. The nitrogen atoms of the imidazole pendent group are coordinated in an axial position, to give a seven-coordinate complex that has distorted pentagonal bipyramidal geometry. In contrast, the Ni(II) ion forms only four bonds to the macrocyclic backbone in addition to the imidazole pendent groups to give a six-coordinate complex. One ether oxygen is not coordinated as the distance between Ni(II) and the oxygen is 2.588 Å, which is longer than a typical N−O bond. This coordination gives rise to a distorted octahedral orientation, with the bond through both imidazole nitrogen atoms coordinated to the nickel center averaging 170° between the two crystallographically distinct complexes that formed in the unit cell. The average bond angle between the nitrogen donor of the imidazole and one of the macrocycle backbone donor groups is approximately 91°. The root-meansquare distance from the plane formed by the macrocyclic backbone donor atoms and for the Ni(II) complex was determined to be 0.218−0.221 Å for the two crystallographically independent complexes. With respect to bond lengths, the metal ions all contain shorter bonds with the pendent imidazoles than with the macrocyclic amines (Table 2). In each of the complexes, the angle of the trans-imidazole pendent groups is close to 180°, at

Figure 2. Crystal structure of [Ni(HINO)](CF3SO3)2. Hydrogen atoms, solvent, and counterions omitted for clarity.

The [Fe(HINO)]2+ and [Co(HINO)]2+ complex cations are each seven-coordinate, with the metal ion bound to two

Figure 3. 1H NMR spectra of (a) [Fe(HINO)]2+, (b) [Co(HINO)]2+, and (c) [Ni(HINO)]2+ in d-acetonitrile. Exchangeable proton marked with an asterisk was determined by addition of D2O to solution. 4549

DOI: 10.1021/acs.inorgchem.7b00176 Inorg. Chem. 2017, 56, 4545−4554

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Inorganic Chemistry 175.14° (N3−Fe−N5), 176.40° (N4−Co−N6), and 170.37° (N5−Ni−N3). For each of the Fe(II), Co(II), and Ni(II) complexes, average bond angles between the pendent imidazole nitrogen to the heteroatom donors on the macrocycle through the metal ion N−M−A (where A is either a nitrogen or oxygen atom on the ring) are 90.4°. The axial bonds between the imidazole pendent arms and the metal center are between 172.36° and 175.14° for the two crystallographically independent complexes of [Fe(HINO)]2+ and 176.40° for [Co(HINO)]2+. Solution Characterization. The 1H NMR spectra of the Co(II) and Ni(II) complexes in acetonitrile produce the expected number of distinct proton resonances (Figure 3). The effective C2 axis of symmetry should give rise to 15 proton resonances if the exchangeable imidazole proton is included. The 1H NMR spectrum of the [Co(HINO)]2+ complex in d6acetonitrile has 15 paramagnetically shifted 1H resonances of equal integration. Likewise, the [Ni(HINO)]2+ 1H NMR spectrum has 13 resonances that are paramagnetically shifted, and also has three additional resonances which are broadened but fall in the diamagnetic region. The [Fe(HINO)]2+ complex shows 12 paramagnetically shifted resonances with one additional resonance in the diamagnetic region which is broadened and assigned to the Fe(II) complex. The reduced number of distinct proton resonances is attributed to the relatively broad peaks for the Fe(II) complex in comparison to the Co(II) and Ni(II) complexes and associated difficulty in resolving and integrating the resonances. The resonances of the complexes range from −23 to 154 ppm for the Ni(II) complex, from −50 to 174 ppm for the Fe(II) complex, and from −5 to −227 ppm for the Co(II) complex. D2O was added to the NMR sample in deuterated acetonitrile (d3-ACN) to identify the exchangeable proton. The exchangeable imidazole NH resonances were at 68 ppm for [Fe(HINO)]2+ and 62 ppm for [Ni(HINO)]2+. For [Co(HINO)]2+, the exchangeable proton was assigned as being in the range 34−37 ppm, as it was difficult to discern which of the several closely spaced resonances in the region was affected by the addition of D2O. The solution chemistry of the complexes was further studied by 1H NMR spectroscopy in H2O and D2O. The magnetic moments of the complexes were measured in solution by using the Evans method.21 [Co(HINO)]2+ and [Ni(HINO)]2+ gave magnetic moments of 4.7 and 3.3 μB, respectively, at 25 °C, and neutral pH. These values are consistent with literature values for high spin complexes of Co(II) or Ni(II), respectively.26 The effective magnetic moment of the [Fe(HINO)]2+ complex in H2O at acidic pH was 5.6 μB. As discussed further below, the propensity of this complex to slowly oxidize in water suggests that this value represents a mixture of high spin Fe(II) and Fe(III) (Figure S3). Notably, high spin complexes of Fe(II) and Fe(III) may have similar effective magnetic moments,2,11,27 although these oxidation states can be distinguished by their different paramagnetic chemical shift and proton relaxation effects.15,27 The 1H NMR spectra of the Co(II) and Ni(II) complexes of HINO in D2O were monitored for the dissociation of the complexes over a 12 h period (Figures S4−S9). Under acidic conditions, the dissociation of the Co(II) complex is negligible (∼2%), and the Ni(II) complex dissociated approximately 5% over 12 h as reported in Table 3. In the presence of an equivalent of ZnCl2, [Co(HINO)]2+ and [Ni(HINO)]2+ undergo slow dissociation over a 12 h period (Table S19) with the Ni(II) complex dissociating to a greater extent. The

Table 3. Comparison of Solution Properties for [M(HINO)]2+ and [M(CYNO)]2+ complex

μeffa

dissociation acidb (%)

signal loss anionsc (%)

dissociation Zn2+d (%)

[Co(HINO)]2+ [Ni(HINO)]2+ [Co(CYNO)]2+e [Ni(CYNO)]2+e

4.6 ± 0.1 3.3 ± 0.1 4.1 3.4

≤2 5 ± 1.8 16 ± 10 18 ± 0.3

14 ± 5f 13 ± 1 0 30

9 ± 3.2 50 ± 18 13 ± 0.1 54 ± 0.6

Effective magnetic moment at 25 °C. b10 mM complex, 100 mM NaCl, and 3−5 mM 3-(trimethylsilyl)-1-propanesulfonic acid sodium salt (TMPSA) in D2O at pD 3.9−4.2. c10 mM complex, 100 mM NaCl, 3−5 mM TMPSA with 0.4 mM PO43−, and 25 mM CO32− in D2O pD 7.5−8. dHINO studied at 10 mM complex, 100 mM NaCl, 5 mM TMPSA, and 5 mM ZnCl2 in D2O pD 6.5−7.0. eData from refs 3, 4, and 17. Ni(II) data were revised to reflect adduct formation as judged from NMR spectra. fNo apparent dissociation, but loss of signal. Data collected at 12 h. a

[Fe(HINO)]2+ complex could not be studied in a similar way as it was unstable in D2O. Over time, the 1H resonances broadened further, and the formation of a precipitate occurred at neutral pH (Figure S3). Also consistent with oxidation of the Fe(II) complex to Fe(III) is the short T1 value observed for an aerated solution of 8 mM complex at pH 3 (T1 = 0.13 ± 0.01 s) which corresponds to values observed for Fe(III) complexes that have no bound water ligand.27 In comparison, the T1 of an 8 mM solution of Fe(III) complex of diethylenetriaminepentaacetic acid (DTPA) which lacks a water ligand was measured to be 0.18 s at 11.7 T, pH 3, and 37 °C, similar to the iron HINO complex. The complexes react slowly in the presence of anions as well, with Co(II) and Ni(II) complexes showing 15% and 13% loss of the intensity of proton resonances, respectively, in the presence of 25 mM carbonate and 0.4 mM phosphate compared to the standard over 12 h at neutral pH. However, there was no indication of dissociation of the complexes under these conditions as judged by the absence of free ligand 1H resonances. A small amount of precipitate was observed for the Co(II) complex, but there was no visible precipitate for the Ni(II) complex. It is likely that carbonate or phosphate anions bind to [Ni(HINO)]2+, but that the proton resonances of the new paramagnetic complex are not sufficiently sharp or intense for detection (Figures S8 and S9). Additional solution studies were carried out by using UV−vis spectroscopy to investigate the speciation in solution as a function of pH. Given the role of the imidazole proton in CEST, assessment of the pKa values is of interest. Titration of [Co(HINO)]2+ led to minimal UV−vis changes in the range 200−700 nm at pH values from 4.8 to 8.5. At pH values greater than 8.5, a color change was observed, but the complex precipitated from solution to prevent a determination of the pKa value. In contrast, titration of [Ni(HINO)]2+ over the same pH range produced a new UV−vis peak at 305 nm. Fitting of the change of absorbance versus pH to a single ionization event gave a pKa of 10.3 (Figure S10). The second imidazole pendent group of this complex presumably ionizes at even higher pH values. CEST NMR Spectroscopy. CEST data were acquired at 1 ppm increments using a presaturation pulse of 24 μT for 4 s at 37 °C. The data are plotted as normalized water signal intensity (Mz/M0) against frequency offset (ppm) as shown in Figure 4. The CEST peak of the [Co(HINO)]2+ complex is observed at 32 ppm from the bulk water signal and is attributed to the 4550

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protons of heterocyclic pendent groups5 and not exchangeable water. Rate constants for chemical exchange of the imidazole NH proton with bulk water were determined by using the Omega plot method (Figures S13 and S14).28 Similar rate constants were obtained if the data were plotted according to the Hanes− Woolf linear QUESP method (Table S20).29 At optimal CEST conditions for the complexes of 7.2, the proton exchange rate constant for both complexes is 1.0 × 103 s−1 (Table S20). The further increase of the proton exchange rate constants with increasing pH is consistent with base-catalyzed exchange. Notably, rapid proton exchange at high pH produces broadening of the CEST peak at pH > 7.2. Further investigations of the nature of the CEST peak were obtained by recording spectra at the lower field strength of 9.4 T (Figure S15). These spectra clearly show that the CEST peaks of both HINO complexes are broadened in comparison to the higher field strength of 11.7 T. These data support exchange broadening of the CEST peak for [Co(HINO)]2+ and [Ni(HINO)]2+ at neutral pH at these field strengths. The CEST spectra of [Co(HINO)]2+ and [Ni(HINO)]2+ were also recorded in the presence of human serum albumin (HSA) (Figures S16 and S17). Spectra of both complexes showed very little change in CEST peak intensity compared to spectra taken in the absence of albumin. Further studies demonstrated that the [Ni(HINO)]2+ complex remained largely intact over 12 h in rabbit serum as shown by the nearly superimposable CEST spectra (Figure S18).

Figure 4. CEST spectra recorded at 11.7 T of 8 mM [Co(HINO)]2+ (blue) or [Ni(HINO)]2+ (green), in solution containing 100 mM NaCl, 20 mM HEPES, at pH 7.0. Radiofrequency pulse of 4 s applied at 37 °C, B1 = 24 μT.

exchangeable NH proton of the imidazole. The Ni(II) complex CEST peak is further shifted and appears at 55 ppm from bulk water. The largest CEST peak intensity is approximately 24% for 8 mM [Co(HINO)]2+ and 25% for 8 mM [Ni(HINO)]2+ in solution. The pH dependence of the CEST peak is shown in Figure 5, and additional data are shown in Supporting

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DISCUSSION Crystal Structures. The [Fe(HINO)] 2+ and [Co(HINO)]2+ complex cations feature seven-coordinate Fe(II) or Co(II), respectively, within a distorted pentagonal bipyramidal geometry. These structures are similar to reported structures of Fe(II) and Co(II) complexes with the 4,10-diaza15-crown-5 macrocycle containing amide pendent groups.17 Other relevant comparisons include Co(II) complexes that contain carboxylate, aniline, or benzimidazole pendent groups on the diazacrown ether, which all exhibit pentagonal bipyramidal geometry.30−32 The [Ni(HINO)]2+ complex cation, on the other hand, does not have a seven-coordinate metal center. The metal ion coordinates through the imidazole pendent groups, and through four of the five donors on the macrocycle. The distance between Ni(II) and the uncoordinated oxygen is 2.588 Å, which is longer than that of a typical N−O bond. The distorted octahedral geometry of [Ni(HINO)]2+ is consistent with reports that show Ni(II) complexes with septadentate macrocyclic ligands form sixcoordinate rather than seven-coordinate complexes.30 Ni(II) complexes of a 4,10-diaza-15-crown-5 macrocycle appended with amides, benzimidazoles, or aminobenzyl groups all have distorted octrahedral geometry.31,32 This distortion has been attributed to the Jahn−Teller effect.30 Solution Characterization. The 1H NMR spectra are consistent with the formation of one predominant species in solution. The Co(II) and Ni(II) complexes of HINO show 15 resonances in acetonitrile and 14 resonances in D2O, consistent with the C2 symmetry of the complex being maintained in solution. The sharp proton resonances that are widely dispersed by the paramagnetic center are reminiscent of the Co(II) and Ni(II) complexes of the CYNO ligand that contains two amide pendent groups. This type of complex shows little dynamic character in solution and gives sharp resonances characteristic

Figure 5. CEST spectrum recorded at 11.7 T of 8 mM [Ni(HINO)]2+ in 100 mM NaCl, 20 mM HEPES, at various pH values (top) and CEST % of Co(II) and Ni(II) complexes as a function of pH (bottom).

Information Figures S11 and S12. There is a gradual increase in intensity from pH 6.8 to 7.2 and then a decrease in intensity from 7.2 to 7.7. The optimal CEST peak intensity is observed at pH 7.2 for both the Co(II) and Ni(II) complexes of HINO. The assignment of the CEST peak to the imidazole proton is based partly on the crystal structures of [Co(HINO]2+ and Ni(HINO)]2+ which show a saturated coordination sphere. There is no bound water, nor any other exchangeable protons other than those of the imidazoles. Furthermore, the pH dependence of the CEST spectrum is characteristic of NH 4551

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Inorganic Chemistry Table 4. Comparison of Co(II) and Ni(II) Complexes of HINO and CYNO complex 2+

[Co(HINO)] [Ni(HINO)]2+ [Co(CYNO)]2+ [Ni(CYNO)]2+

CESTa %

kex (s‑1)

22.8 ± 0.4 23 ± 1.3d 38e 39e

1020 ± 84 1030 ± 54d 240 ± 70e 240 ± 20e

d

d

T1b (s)

NMR 1H fwhm (Hz)c

0.864 ± 0.004 0.963 ± 0.073 1.44 ± 0.07 1.12 ± 0.19

84−560 48−360 80−400 68−440

CEST spectra on 11.7 T NMR, presaturation pulse 24 μT, 100 mM NaCl, 20 mM HEPES buffer, 37 °C, and 8−10 mM complex. b8 mM complex, 100 mM NaCl, 20 mM HEPES buffer pH 7.3−7.4, 37 °C, measured on 11.7 T NMR. cMeasured on 9.4 T NMR. d8 mM complex, 100 mM NaCl, 20 mM HEPES pH 7.2, 37 °C. epH 7.4. From refs 3, 4, and 17. a

effect.34 In fact, the opposite trend is observed despite the similarity of the solution and magnetic properties of the complexes. Similar properties include the peak widths of the proton resonances for [Ni(HINO)]2+ and [Co(HINO)]2+ which range from 48 to 360 Hz and from 84 to 560 Hz, respectively, similar to those of the [Co(CYNO)]2+ and [Ni(CYNO)]2+ complexes at 80−400 Hz and 68−440 Hz, suggesting that dynamic processes involving the macrocycle or other T2 effects are not the predominant contributing factors.35 The T1 values for [Co(HINO)]2+ (0.864 ± 0.004 s) and [Ni(HINO)]2+ (0.963 ± 0.073 s) are similar to those of [Co(CYNO)]2+ (1.44 ± 0.07 s) and [Ni(CYNO)]2+ (1.12 ± 0.19 s) for solutions at pH 7.4 and 8 mM complex. These similarities suggest that differences in relaxivity do not contribute substantially to the observed differences in CEST peak intensity. One important contributing factor to the broader and less intense CEST peak of the [Ni(HINO)]2+ and [Co(HINO)]2+ complexes is exchange broadening due to the smaller shifts of the imidazole protons on the HINO complexes and their relatively rapid exchange rate constants. Consistent with this postulate, CEST spectra of the HINO complexes were even broader at the lower field strength of 9.4 T in comparison to 11.7 T, while the intensity and width of the CEST peaks of the CYNO complexes remained relatively constant at the two field strengths. Despite the fact that the exchange rate constants of the HINO complexes are too large to produce an optimal CEST effect given the modest CEST peak shift, these rate constants and their pH dependence are nonetheless in a desirable range for in vivo studies. Notably, the relatively high pKa value of 10.3 for the [Ni(HINO]2+ complex ensures that both imidazole groups are protonated at neutral pH. Rate constants of 1.0 × 103 s−1 at pH = 7.2 are close to optimal for CEST imaging in vivo.19 The relationship kex = 2πB (where B is pulse power in Hz) gives optimal exchange rate constants for a particular pulse power. The highest pulse power that can be used in animal studies is about 200 Hz or 5 μT, so that the rate constant should be no more than 1300 s−1. Thus, the imidazole pendent groups are optimized for CEST in animals from the standpoint of the magnitude of the rate constants at neutral pH, although the paramagnetic chemical shift must be increased.

of a single conformer. The narrow line widths of the resonances are especially surprising for the Ni(II) complexes given that many six-coordinate Ni(II) complexes have long electronic relaxation times and correspondingly broad proton resonances.33 In contrast, the Fe(II) complex of HINO has relatively broad 1H resonances that broaden further over time, consistent with the oxidation of the Fe(II) to Fe(III). This oxidation was sufficiently rapid in water to prevent the observation of a CEST peak. By comparison, the Fe(II) complex of CYNO, which contains amide pendent groups, was sufficiently stable for CEST NMR and MRI studies.17 Dissociation of the Co(II) and Ni(II) complexes of HINO were compared to that of the analogous CYNO complexes (Table 3). The [Co(HINO)]2+ and [Ni(HINO)]2+ complexes in D2O at neutral pD were inert to dissociation for several days as judged by 1H NMR spectroscopy. Both Co(II) and Ni(II) complexes of HINO remain relatively intact when incubated at 37 °C in acid for 12 h, but undergo a slow dissociation over the course of several hours in the presence of an equivalent of Zn(II) (10 mM, Table S19). These data show that the HINO complexes are more kinetically inert than the CYNO complexes toward acid, but similarly prone to transmetalation. Similar to the CYNO complexes, [Co(HINO)]2+ and [Ni(HINO)]2+ complexes do not dissociate in the presence of anions, although there is some loss of proton resonance intensity that suggests interaction with the anions. It was reported previously that the [Ni(CYNO)]2+ complex formed an adduct with carbonate, as shown by new paramagnetically shifted proton resonances.4 Studies in the presence of human serum albumin (HSA) or blood serum showed that [Ni(HINO)]2+ was more inert than [Ni(CYNO)]2+. Whereas interaction of [Ni(CYNO)]2+ in serum leads to a nearly total loss of the CEST peak,17 the [Ni(HINO)]2+ CEST effect is relatively unchanged. This result together with the dissociation data suggests that the imidazole groups bind more tightly to Co(II) and Ni(II) than do the amide groups in CYNO. CEST Spectroscopy Comparison. It is of interest to compare the CEST spectra of the HINO complexes with that of their CYNO analogues (Table 4). The Co(II) and Ni(II) complexes of HINO each have two chemically equivalent exchangeable NH protons that give rise to a single CEST peak. In contrast, the Co(II) and Ni(II) complexes of CYNO have two sets of amide protons that give rise to two CEST peaks for each complex. Comparison is made to the furthest shifted CEST peak for the CYNO complexes in Table 4. Thus, the CEST peak of all four complexes arises from the exchange of two protons. Given the equivalent numbers of protons giving rise to CEST, the two types of complexes, CYNO and HINO, might be expected to have similar CEST peak intensities. Furthermore, the larger rate constant for exchange of the HINO complexes in comparison to those of the CYNO complexes might be expected to produce a larger CEST

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CONCLUSIONS Fe(II), Co(II), and Ni(II) complexes of HINO have sharp, highly shifted 1H resonances that facilitate the study of imidazole pendent groups for paraCEST agents. Interestingly, the imidazole pendent groups stabilize the Ni(II) complex with respect to amide groups both in acid and in the presence of serum. The imidazole groups in [Co(HINO)]2+ also serve to make the Co(II) complex more inert in acid in comparison to the analogous amide complex. However, HINO does not give stable complexes with Fe(II) in water at neutral pH. The Fe(II) 4552

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(4) Olatunde, A. O.; Dorazio, S. J.; Spernyak, J. A.; Morrow, J. R. The NiCEST Approach: Nickel(II) ParaCEST MRI Contrast Agents. J. Am. Chem. Soc. 2012, 134 (45), 18503−5. (5) Tsitovich, P. B.; Spernyak, J. A.; Morrow, J. R. A Redox-Activated MRI Contrast Agent that Switches Between Paramagnetic and Diamagnetic States. Angew. Chem., Int. Ed. 2013, 52 (52), 13997− 4000. (6) Morrow, J. R.; Tsitovich, P. B. Transition Metal PARACEST Probes: Alternatives to Lanthanides. In Chemical Exchange Saturation Transfer Imaging: Advances and Applications; McMahon, M. T., Gilad, A. A., Bulte, J. W. M., van Zijl, P. C., Eds.; Pan Stanford, 2016; pp 257−282. (7) Viswanathan, S.; Kovacs, Z.; Green, K. N.; Ratnakar, S. J.; Sherry, A. D. Alternatives to Gadolinium-Based Metal Chelates for Magnetic Resonance Imaging. Chem. Rev. 2010, 110 (5), 2960−3018. (8) Terreno, E.; Castelli, D. D.; Aime, S. Encoding the Frequency Dependence in MRI Contrast Media: the Emerging Class of CEST Agents. Contrast Media Mol. Imaging 2010, 5 (2), 78−98. (9) Dorazio, S. J.; Morrow, J. R. Iron(II) Complexes Containing Octadentate Tetraazamacrocycles as ParaCEST Magnetic Resonance Imaging Contrast Agents. Inorg. Chem. 2012, 51 (14), 7448−7450. (10) Olatunde, A. O.; Bond, C. J.; Dorazio, S. J.; Cox, J. M.; Benedict, J. B.; Daddario, M. D.; Spernyak, J. A.; Morrow, J. R. Six, Seven or Eight Coordinate Fe(II), Co(II) or Ni(II) Complexes of AmideAppended Tetraazamacrocycles for ParaCEST Thermometry. Chem. Eur. J. 2015, 21 (50), 18290−300. (11) Tsitovich, P. B.; Cox, J. M.; Spernyak, J. A.; Morrow, J. R. Gear up for a pH Shift: a Resonpsive Iron(II) 2-amino-6-picolyl-Appended Macrocyclic ParaCEST Agent that Protonates at a Pendent Group. Inorg. Chem. 2016, 55 (22), 12001−10. (12) Jeon, I.-R.; Park, J. G.; Haney, C. R.; Harris, T. D. Spin Crossover Iron(II) Complexes as PARACEST MRI Thermometers. Chem. Sci. 2014, 5, 2461−2465. (13) Harvey, P.; Blamire, A. M.; Wilson, J. I.; Finney, K.-L. N. A.; Funk, A. M.; Senanayake, P. K.; Parker, D. Moving the Goal Posts: Enhancing the Sensitivity of PARASHIFT Proton Magnetic Resonance Imaging and Spectroscopy. Chem. Sci. 2013, 4, 4251−4258. (14) Tsitovich, P. B.; Morrow, J. R. Macrocyclic Ligands for Fe(II) ParaCEST and Chemical Shift MRI Contrast Agents. Inorg. Chim. Acta 2012, 393, 3−11. (15) Tsitovich, P. B.; Cox, J. M.; Benedict, J. B.; Morrow, J. R. Sixcoordinate Iron(II) and Cobalt(II) paraSHIFT Agents for Measuring Temperature by Magnetic Resonance Spectroscopy. Inorg. Chem. 2016, 55 (2), 700−16. (16) Dorazio, S. J.; Tsitovich, P. B.; Gardina, S. A.; Morrow, J. R. The Reactivity of Macrocyclic Fe(II) ParaCEST MRI Contrast Agents towards Biologically Relevant Anions, Cations, Oxygen or Peroxide. J. Inorg. Biochem. 2012, 117, 212−9. (17) Olatunde, A. O.; Cox, J. M.; Daddario, M. D.; Spernyak, J. A.; Benedict, J. B.; Morrow, J. R. Seven-Coordinate CoII, FeII and SixCoordinate NiII Amide-Appended Macrocyclic Complexes as ParaCEST Agents in Biological Media. Inorg. Chem. 2014, 53 (16), 8311−21. (18) He, J.; Bonnet, C. S.; Eliseeva, S. V.; Lacerda, S.; Chauvin, T.; Retailleau, P.; Szeremeta, F.; Badet, B.; Petoud, S.; Toth, E.; Durand, P. Prototypes of Lanthanide(III) Agents Responsive to Enzymatic Activities in Three Complementary Imaging Modalities: Visible/NearInfrared Luminescence, PARACEST-, and T1-MRI. J. Am. Chem. Soc. 2016, 138 (9), 2913−6. (19) Woessner, D. E.; Zhang, S. R.; Merritt, M. E.; Sherry, A. D. Numerical Solution of the Bloch Equations Provides Insights into the Optimum Design of PARACEST Agents for MRI. Magn. Reson. Med. 2005, 53 (4), 790−9. (20) Yang, X.; Song, X. L.; Banerjee, S. R.; Li, Y. G.; Byun, Y.; Liu, G. S.; Bhujwalla, Z. M.; Pomper, M. G.; McMahon, M. T. Developing Imidazoles as CEST MRI pH Sensors. Contrast Media Mol. Imaging 2016, 11 (4), 304−312.

complex with the imidazole pendent groups oxidizes readily in aqueous solution, in comparison to the analogous complex with amide pendent groups.17 The NH protons of the imidazole pendent groups in the [Fe(HINO)]2+, [Co(HINO)]2+, or [Ni(HINO)]2+ complexes are not highly paramagnetically shifted. This is not perhaps surprising for the Fe(II) or Co(II) complex from the standpoint of coordination geometry. The largest paramagnetic induced shifts for exchangeable proton resonances for Fe(II) or Co(II) paraCEST agents reported to date are associated with six-coordinate complexes,5,10 not with seven-coordinate complexes.10,17 Six-coordinate complexes of Fe(II) or Co(II) with distorted octahedral geometry show large paramagnetic induced proton shifts, suggesting that both through bond and through space contributions are more effective with the shorter bond distances of the lower coordination number.11,15 Future studies will investigate imidazole pendent groups in different coordination environments including in octahedral complexes. The nearly optimal exchange rate constants and pH dependence for the CEST effect of imidazole pendent groups in transition metal complexes suggest that these groups will be useful for the development of paraCEST agents.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b00176. Experimental details including NMR spectra, CEST spectra, Omega plots to obtain exchange rate constants, and synthetic procedures (PDF) Crystallographic details for [Co(HINO)](CoCl4)·H2O (CIF) Crystallographic details for [Fe(HINO)](CF3SO3)2 (CIF) Crystallographic details for [Ni(HINO)](CF3SO3)2 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: jmorrow@buffalo.edu. Fax: 716-645-6963. ORCID

Janet R. Morrow: 0000-0003-4160-7688 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS J.R.M. thanks the NSF (CHE-1310374) for support of this work.

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REFERENCES

(1) Dorazio, S. J.; Olatunde, A. O.; Tsitovich, P. B.; Morrow, J. R. Comparison of Divalent Transition Metal Ion paraCEST MRI Contrast Agents. J. Biol. Inorg. Chem. 2014, 19 (2), 191−205. (2) Dorazio, S. J.; Tsitovich, P. B.; Siters, K. E.; Spernyak, J. A.; Morrow, J. R. Iron(II) PARACEST MRI Contrast Agents. J. Am. Chem. Soc. 2011, 133 (36), 14154−6. (3) Dorazio, S. J.; Olatunde, A. O.; Spernyak, J. A.; Morrow, J. R. CoCEST: Cobalt(II) Amide-Appended ParaCEST MRI Contrast Agents. Chem. Commun. 2013, 49 (85), 10025−7. 4553

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