Inner-Sphere and Outer-Sphere Water Interactions in Co(II) paraCEST

Feb 7, 2018 - Synopsis. Four macrocyclic complexes of Co(II) that contain amide or alcohol pendents were studied as paraCEST agents and as ...
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Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Inner-Sphere and Outer-Sphere Water Interactions in Co(II) paraCEST Agents Samira M. Abozeid,† Eric M. Snyder,† Timothy Y. Tittiris,† Charles M. Steuerwald,† Alexander Y. Nazarenko,‡ and Janet R. Morrow*,† †

Department of Chemistry, University at Buffalo, State University of New York, Amherst, New York 14260, United States Chemistry Department, SUNY College at Buffalo, 1300 Elmwood Avenue, Buffalo, New York 14222, United States

‡

S Supporting Information *

ABSTRACT: High-spin Co(II) complexes are promising for development as paraCEST agents (paraCEST = paramagnetic chemical exchange saturation transfer) for magnetic resonance imaging applications. The first examples of Co(II) paraCEST agents with bound water ligands are presented here. Four Co(II) macrocyclic complexes based on 1,4,7triazacyclononane and containing either pendent alcohol or pendent amide groups were prepared. Two of the macrocycles encapsulate the Co(II) and contain no water ligands as shown by X-ray crystallographic studies, and two complexes have macrocycles with only five ligand donor groups to leave an open coordination site for bound water. The ionization of alcohol, water, or amide groups in the complexes was characterized by using pH potentiometry. These data show that one of the complexes has a readily deprotonated group with a pKa close to 6, which is assigned as an alcohol pendent. Amide pendents deprotonate at high pH (>8), and the water ligands of the Co(II) complexes are not deprotonated at neutral pH. All complexes produce CEST peaks through either alcohol OH or amide NH proton exchange. The water ligands exchange too rapidly to produce a CEST effect as shown by variable-temperature 17O NMR spectroscopy studies. The complexes with available coordination sites for inner-sphere water ligands produce large paramagnetic shifts and broadening of the 17O resonances of bulk water, whereas the encapsulated complexes show much less shifting and broadening of 17O resonances. All complexes produce substantial paramagnetic shifts of the 1H resonances of bulk water, which is promising for the development of supramolecular CEST agents.

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INTRODUCTION Paramagnetic transition-metal ion complexes are of interest in the development of paraCEST (paraCEST = paramagnetic chemical exchange saturation transfer) agents for magnetic resonance imaging (MRI) applications.1−3 Metal ion complexes that act as paraCEST agents produce highly shifted but relatively sharp proton resonances. Lanthanide(III) complexes have traditionally been used as paraCEST agents,4−13 but more recently transition-metal ion complexes including those of Fe(II), Fe(III), Cu(II), Ni(II), and Co(II) have been reported.14−16 High-spin Co(II) complexes are of special interest given the possibility of redox-responsive switching upon oxidation to diamagnetic Co(III) complexes.17 ParaCEST agents contain exchangeable protons, typically NH or OH protons on ligands.18,19 Irradiation of the exchangeable proton with a presaturation radio frequency pulse leads to magnetic saturation of the proton and a decrease in water proton resonance signal upon exchange.20 Co(II) paraCEST20 agents reported to date typically are encapsulated by a macrocyclic ligand and have exchangeable amide NH, alcohol OH, or heterocyclic NH protons.3,21−25 There are no examples of exchangeable water ligands on Co(II) complexes that produce CEST peaks, to the best of our knowledge. In contrast, Ln(III) paraCEST agents frequently © XXXX American Chemical Society

have a slowly exchanging water ligand that gives rise to a CEST peak.26 The water exchange rate constant in these Ln(III) complexes ranges from 1400 to 6200 s−1.27 Notably, the relatively slow rate of water exchange in these complexes is necessary to observe the CEST peak. This is due to the consideration that the separation of the bulk water and exchangeable proton frequency (Δω) must be greater than the exchange rate constant (kex).28 For the design of Co(II) complexes that produce the CEST effect through water exchange, the water exchange rate constant must similarly be slow. Rate constants for the Co(II) aqua complex are on the order of 1 × 106 s−1 and are exchanging too rapidly to give rise to CEST peaks for typical Δω values.29 A disadvantage of paraCEST agents is their low sensitivity in comparison to T1 MRI contrast agents.30 Supramolecular CEST agents31−41 are a means of overcoming the low sensitivity of paraCEST agents. The supramolecular assemblies that contain paramagnetic complexes may be based on liposomes (lipoCEST),42−44 protein aggregates,39 or mesoporous silica nanoparticles.45 A common feature of these supramolecular agents is that the paramagnetic complex shifts Received: November 22, 2017

A

DOI: 10.1021/acs.inorgchem.7b02977 Inorg. Chem. XXXX, XXX, XXX−XXX

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similar complex containing a different counterion was reported several years ago.46 The crystal structures of [Co(L3)](ClO4)2 and [Co(L3)](NO3)2 show six-coordinate Co(II) centers with three oxygen and three nitrogen donors (Figure 1 and Figure S29). Selected

the proton resonances of multiple OH groups such as water in the interior of the liposome or OH groups on the surface of silica. The paraCEST agents that are reported in supramolecular systems are lanthanide(III)-based and typically have an open coordination site.45 Transition-metal ions might also be used as supramolecular CEST agents if they had an open coordination site for exchange of water or hydroxyl groups. In this study, we present four Co(II) complexes that contain either alcohol or amide pendents as paraCEST agents (Scheme 1). Two Co(II) complexes contain classical sexadentate Scheme 1

macrocyclic ligands L1 and L3, which have been previously reported.46,47 These complexes are compared to two new complexes that have pentadentate macrocyclic ligands that bind to Co(II) and leave open coordination sites for bound water. The presence of an inner-sphere water ligand is probed by using variable-temperature 17O NMR spectroscopy studies. As expected, inner-sphere water ligands contribute to hyperfine shifting of water proton resonances in Co(II) complexes, but there is also an unexpectedly large contribution from outersphere interactions to the paramagnetic shifts of 1H NMR water resonances, which may be useful in the preparation of supramolecular agents. These interactions most reasonably involve second-sphere water molecules that interact strongly with pendent alcohol or amide groups through hydrogen bonding.

Figure 1. Molecular structure of the complex cation of [Co(L3)](ClO4)2 showing the atom-labeling scheme and 50% probability displacement ellipsoids.

bond lengths and angles are given in Table S9. The complexes are distorted trigonal prismatic with a twist angle of 18(2)° or 17(2)° between the trigonal planes for [Co(L3)](NO3)2 and [Co(L3)](ClO4) 2, respectively. The Ni(II) and Zn(II) complexes of L3 are structurally similar to that of the Co(II) complex reported here.47,48 Supramolecular features of these complexes demonstrate extensive hydrogen-bonding interactions between one of the hydrogen atoms of an amide NH group and a carbonyl oxygen of another complex cation as described in the supplementary section (Table S11, Figures S32−S37). NMR Spectroscopy Studies. 1H NMR spectroscopy studies support the presence of high-spin Co(II) complexes in solution. Magnetic moments of the Co(II) complexes, as measured by Evans method49 with a diamagnetic correction,50 were μeff = 4.67 ± 0.09, 4.60 ± 0.05, 4.56 ± 0.08, 4.79 ± 0.25 BM at 25 °C for [Co(L1)]2+ [Co(L2)]2+, [Co(L3)]2+, and [Co(L4)]2+, respectively. These values are typical of high-spin Co(II) complexes that exhibit substantial spin−orbit coupling and thus have higher magnetic moments than predicted from the spin-only values.21,51,52 The 1H NMR resonances of [Co(L1)]2+ and [Co(L2)]2+ are relatively sharp and highly paramagnetically shifted (Figures 2, S1, and S2). 1H NMR spectra span the range from −95 to +225 ppm for [Co(L1)]2+. The hyperfine-shifted proton resonances of [Co(L2)]2+ span an even greater range from −93 to 266 ppm. [Co(L1)]2+ shows six proton resonances of approximately equal intensity and one resonance with threefold greater intensity close to the diamagnetic region that was assigned to the methyl protons. The seven distinct proton resonances that are observed are consistent with that expected for a single diastereomer of [Co(L1)]2+. The 1H NMR spectrum of [Co(L2)]2+ in D2O consists of 19 distinct proton resonances of unequal integration. The resonances at 17.5 ppm integrate to three protons and are assigned to the two CH3

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RESULTS Preparation and Structure of the Complexes. The four macrocyclic ligands that were prepared contained either amide or alcohol pendent groups (Scheme 1). Addition of three pendent groups to 1,4,7-triazacyclononane (TACN) produced hexadentate ligands (L1 and L3), whereas addition of two pendents to benzyl-appended TACN produced two pentadentate ligands (L2 and L4). Both CoCl2 and Co(NO3)2 salts were used to prepare the Co(II) complexes. The use of CoCl2 produced CoCl42− that crystallized as the counterion in [Co(L1)]CoCl4. For solution studies, nitrate salts of Co(II) were used to avoid the complicating effects of the CoCl42− anion in magnetic moment measurements, NMR spectra, or CEST spectra. The [Co(L3)]2+ complex was prepared as the nitrate salt for solution studies, but it was also prepared as the perchlorate salt. The X-ray crystal structure of [Co(L1)]CoCl4 features a sixcoordinate Co(II) complex cation with three macrocyclic nitrogen donors and three alcohol pendent oxygen donors (Figure S29). The [Co(L1)]2+ complex cation has a distorted trigonal prismatic geometry with an angle of 38(1)° between the two trigonal planes formed from the three nitrogen atoms and the three oxygen atoms (Figure S30). Selected bond lengths and angles are given in Table S9. The [Co(L1)]2+ complex cation shows hydrogen bonding between alcohol groups of the Co(II) complex and three of the chlorides of the CoCl42− counterion (Figures S32 and S33). The structure of a B

DOI: 10.1021/acs.inorgchem.7b02977 Inorg. Chem. XXXX, XXX, XXX−XXX

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Figure 2. 1H NMR of [Co(L2)]2+ in D2O, pD 5.8 at 25 °C.

were close to 20% dissociated in acid after 18 h. Data are compiled in Table S1 and shown in Figure S6. Further studies were performed with 1−10 equiv of Cu(II) as a competitor to investigate transmetalation processes (Figures S8−S10). These studies showed no detectable dissociation of [Co(L1)]2+ or [Co(L4)]2+ to produce Cu(II) complexes in the presence of a 1:1 ratio with Cu(NO3)2 after incubation at 37 °C over a 3 h period. [Co(L2)]2+, however, showed a few percent dissociation (9%) under these conditions. A 10-fold excess of Cu(II) produces moderate dissociation (9−16%) in the three complexes over 3 h at 37 °C. Solution pH-Potentiometric Titrations. The solution chemistry of the complexes was further examined by pHpotentiometric titrations to determine the equilibrium constants for deprotonation of alcohol, amide, or water ligands. The raw data are shown in Figures S11 and S12, and the various equilibria are defined in Table S2 with the corresponding equilibrium constants in Table 1. Speciation

protons on the coordinating pendents, and the resonances at 13.0 ppm integrate to 5 protons, assigned to the benzyl protons on the noncoordinating pendent. Resonances located at −24.5, −93.0, and 144.5 ppm integrate to two protons. These resonances most likely arise from protons of the two different pendent alcohol groups, which are in similar, although not symmetrically related, environments. Thus, there are two overlapping protons (CH(Me)) of the pendent and a set of two for the diastereotopic CH2 protons. The remaining proton resonances have relative integration values of 1 and represent inequivalent CH2 protons on the macrocycle backbone and the noncoordinating pendent. Taken together, these data suggest that there are 31 nonexchangeable protons represented in the spectrum with a few overlapping resonances to give 19 proton resonances of unequal intensity. This 1H NMR spectrum is most consistent with a single diastereomeric form that is rigid on the NMR time scale. In contrast, the 1H NMR spectrum of [Co(L4)]2+ showed severely broadened resonances. The appearance of the 1H NMR spectrum of this complex is similar to that of [Co(L3)]2+, which shows broadened resonances that have been attributed to dynamic solution processes.3 1 H NMR spectroscopy was used to study the kinetic inertness of the complexes toward dissociation at neutral pH in the presence of biologically relevant concentrations of phosphate (0.4 mM) and carbonate (24 mM) at 37 °C (Table S1, Figure S7).24 The [Co(L1)]2+ complex showed no dissociation over 18 h, whereas [Co(L2)]2+ was more labile with 10% dissociation upon incubation over 18 h. An additional concern was whether the open coordination site would facilitate oxidation of the Co(II). Notably, the diamagnetic region of the 1 H NMR spectrum of [Co(L2)]2+ or [Co(L4)]2+ did not show any 1H resonances that could be attributed to diamagnetic Co(III) complexes for [Co(L2)]2+ or [Co(L4)]2+ (Figures S2− S5). Furthermore, the 1H NMR spectra of these complexes in D2O did not change when incubated over a couple of days, consistent with inertness of these complexes toward oxidation. Transmetalation by other metal cations and acidic conditions were also studied. [Co(L1)]2+ showed little dissociation in the presence of 10 equiv of Zn(II), whereas [Co(L2)]2+ showed 12% after 18 h. Acid-catalyzed dissociation at pD 3.4 showed that the [Co(L1)]2+, [Co(L2)]2+, and [Co(L4)]2+ complexes

Table 1. pKa Values of Exchangeable Protons from Potentiometric Titrations at 25 °C, in 0.10 M NaCl equilibria log log log log

K1 K2 K3 K4

[Co(L1)]2+

[Co(L2)]2+

[Co(L3)]2+

[Co(L4)]2+

9.86 ± 0.1 8.87 ± 0.1 5.75 ± 0.2

9.70 ± 0.1 8.49 ± 0.1

9.74 ± 0.1 8.71 ± 0.1

9.32 9.00 8.89 7.94

± ± ± ±

0.1 0.2 0.2 0.2

diagrams are in Figures S13 and S14. The [Co(L1)]2+ complex is the only complex that has a deprotonated ligand at neutral pH. For [Co(L1)]3+, the deprotonation with a pKa of 5.8 is attributed to an alcohol pendent, given that there are no other ionizable groups. Two further ionizations are found with pKa values of 8.9 and 9.9, which are also assigned to the alcohol groups. In contrast, [Co(L2)]2+ showed no ionizations in the neutral pH range but had two ionizations at pH > 8. These deprotonation events are attributed to either alcohol pendents or to a water ligand. The two amide complexes showed ionizations with high pKa values. [Co(L3)]2+ had two pKa values that were greater than 8.5 that are assigned to deprotonation of amide groups. [Co(L4)]2+ had the most C

DOI: 10.1021/acs.inorgchem.7b02977 Inorg. Chem. XXXX, XXX, XXX−XXX

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Figure 3. CEST spectra of (A) 8 mM [Co(L1)]2+. (inset) pH dependence of CEST spectrum. (B) 10 mM Co(L2)]2+. Samples contained 20 mM buffer MES, 100 mM NaCl. B1 = 760 Hz (18 μT) or 440 Hz (10 μT), respectively, applied for 2 s at 37 °C and 11.7 T.

Figure 4. Shift and line-broadening of the 17O resonance of a 100 mM [Co(L1)]2+ (A), [Co(L3)]2+ (B), [Co(L2)]2+ (C), and [Co(L4)]2+ (D) solutions at variable temperatures and pH 6.

interesting pH titration data with four high pKa values. The first one at pKa = 7.94 is most likely the bound water molecule. This complex has two amide pendents that may give two more ionizations. The presence of a fourth ionization is consistent with a second water ligand in a seven-coordinate species. Macrocyclic complexes of Co(II) with amide pendents are occasionally seven-coordinate.21,22 As shown below, the presence of two water ligands is also supported by the much larger line broadening and shifts of the 17O NMR resonances than observed with [Co(L2)]2+. UV−Vis Spectroscopy. The UV−vis spectra for all four complexes are shown in Figure S15. The small extinction coefficients (1000 nm). These differences are consistent with a change in donor strength upon substitution of an amide with a water ligand and also possible changes in coordination geometry in solution as described below. CEST Spectra. CEST spectra,1,23,58,59 plotted as the percent decrease in water proton magnetization as a function of presaturation pulse frequency, were recorded for [Co(L1)]2+, [Co(L2)]2+, and [Co(L4)]2+ (Figures 3 and S16). The most remarkable CEST spectrum is observed for [Co(L1)]2+, where the CEST peak is shifted 140 ppm from the bulk water proton resonance. An increase in intensity is observed from pH 4 to 6.8, followed by a decrease in intensity with a slight broadening of the peak, which is observed at pH values above 6.8 (Figure S17). The relatively large rate constants for alcohol OH exchange for [Co(L1)]2+, which increase from 1070 s−1 at pH 5.8 to 5000 s−1 at pH 7.5, are characteristic of alcohol OH proton exchange in transition-metal complexes (Figures S18 and S19).14 The slight broadening at the highest pH values measured is consistent with exchange being too rapid to D

DOI: 10.1021/acs.inorgchem.7b02977 Inorg. Chem. XXXX, XXX, XXX−XXX

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Figure 5. (A) Transverse 17O relaxivity, ln(1/T2r), as a function of temperature (top) for [Co(L4)]2+, 17O reduced chemical shift as a function of temperature (bottom) for [Co(L4)]2+. (B) Transverse 17O NMR relaxivity, ln(1/T2r), as a function of temperature (top) for [Co(L1)]2+, 17O reduced chemical shift as a function of temperature (bottom) for [Co(L1)]2+. All solutions were at pH 6. Solid lines represent fits to the data (see Supporting Information).

Figure 6. (A) Concentration dependence on 17O NMR chemical shift at 60 °C and (B) concentration dependence on 1H NMR chemical shift at 25 °C.

Variable-Temperature 17O and 1H NMR Spectroscopy. Variable-temperature 17O NMR studies were performed on all four complexes to characterize their interactions with bulk water, including the determination of water exchange rate constants for complexes containing bound water. Plots showing 17 O NMR spectra over the temperature range from 25 to 80 °C are shown in Figure 4. Interestingly, both [Co(L2)]2+ and [Co(L4)]2+ substantially broadened and shifted the 17O NMR water resonance, as expected for paramagnetic complexes with inner-sphere water ligands.61−63 In contrast, [Co(L3)]2+ barely shifts and does not substantially broaden the 17O NMR resonance of water. This result is consistent with a complex that lacks an open coordination site for water ligands. [Co(L1)]2+ shows intermediate behavior such that the 17O NMR resonance broadens and shifts with temperature more than it does for [Co(L3)]2+ but far less than it does with [Co(L2)2+ or [Co(L4)]2+. A plot of the 17O resonance peak width as a function of complex concentration shows that [Co(L4)]2+ followed by [Co(L2)]2+ has the largest slope (Figure S25). Both the transverse relaxation times (T2r) and the chemical shifts of the 17O NMR resonances (Δωr) in the presence of Co(II) complexes as a function of temperature were recorded. These data were fit to the Swift−Connick equations61,64 (Supporting Information eqs S1−S6). [Co(L4)]2+ gave a plot of ln(1/T2r) versus temperature that had the most pronounced

produce optimal CEST peak intensities, even for this highly shifted peak.60 The CEST spectrum for [Co(L2)]2+ is quite different from that of [Co(L1)]2+ (Figure 3). The CEST peak of [Co(L2)]2+ is of lowered intensity and, at 37 ppm versus bulk water, is not highly shifted. The CEST peak intensity increases from pH 5 to 5.8, then broadens and decreases in intensity at pH values higher than 6.4 (Figure S20). The exchange rate constants increase from 1200 s−1 at pH 5.8 to 4000 s−1 at pH 7 (Table S3, Figure S22). The pH dependence and magnitude of the rate constant is consistent with alcohol OH exchange.1,14 Both [Co(L1)]2+ and [Co(L2)]2+ showed little to no change in CEST peak intensity in the presence of 0.4 mM phosphate and 25 mM carbonate Figures S23 and S24). The possibility that water ligand exchange was sufficiently slow on the NMR time scale ( 8), and suggest that neither amide groups nor water ligands are deprotonated at neutral pH values. That a Co(II) water ligand would have a pKa value of 8 is not remarkable based on known values.68,69 Notably, analogous macrocyclic complexes of Zn(II) have water pKa values that range from 7.3 to 9.3.70,71 Co(II) Water Exchange. Early studies of water ligand exchange suggested that rate constants are relatively rapid (>1 × 106 s−1) for the Co(II) aqua ion.72 A more recent study of Co(II) in heteropolyoxotungstates73 gave rate constants of (1.5−1.6) × 106 s−1 for water exchange. The rate constants observed here for [Co(L4)]2+ and [Co(L2)]2+ at 1.5 × 106 and 1.3 × 106 s−1 (for q = 2 and 1, respectively) are in a similar range. However, these rate constants are too large to produce a CEST peak, given that the Δω would need to be several thousand parts per million on a 500 MHz NMR spectrometer. Toward producing a CEST water peak, the rate of water exchange might be decreased by modification of the Co(II) complexes. In Ln(III) complexes, bound water exchange rate constants are slowed in complexes that have a single water ligand by incorporation of multiple adjacent donor groups that are in close proximity to the water ligand.26 Reported [Eu(DOTA)(OH2)]− derivatives having glutamyl-phosphonate side arms on amide pendents display the slowest water exchange rates of any other paraCEST agent reported to date

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CONCLUSIONS The four complexes in this study were prepared with the goal of studying the effect of inner-sphere water ligands on Co(II)based paraCEST agents. There was no detectable CEST effect from exchange of bound water at 11.7 T, but CEST peaks for amide NH and for alcohol OH were observed for all complexes. G

DOI: 10.1021/acs.inorgchem.7b02977 Inorg. Chem. XXXX, XXX, XXX−XXX

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benzyl pendent), δ 63.8 (2C, CH2 alcohol pendents), δ 66.4 (2C, CH alcohol pendents), and δ 127.1, 128.2, 129.6, 139.2 (C6H5 benzene ring). Synthesis of L4. In a 10 mL round-bottom flask, 1-benzyl-[1,4,7]triazacyclononane (0.250 g, 1.14 mmol) was dissolved in 5.0 mL of acetonitrile. To this solution, 5 mL of acetonitrile solution of 2bromoacetamide (0.362g, 2.623 mmol) was added followed by Nethyldiisopropylamine (0.88 mL, 5.10 mmol), which was added dropwise over several minutes. Following addition, the mixture was heated for 3 h at 60 °C followed by stirring overnight. The solvent was decanted from the precipitate, and the white precipitate was washed with acetonitrile, then with ether, and dried under vacuum. Yield: 94%. ESI-MS: m/z = 334.3 (100%) [M + H]+; 356.3 (30%) [M + Na]+. 1H NMR (400 MHz, (deuterated dimethyl sulfoxide (d6-DMSO)); δ 7 (4H, -NH2 amides), δ 7.21, 7.30, 7.53 (5H, −5CH benzene ring), δ 3.62, 3.59 (2H, −CH2 benzyl), δ 3.01 (4H, −2CH2 alcohol pendents), and δ 2.71, 2.64 (12H, −6CH2 macrocycle). 13C NMR (300 MHz, d6DMSO): δ = 127.3, 128.6, 129.5, 139.945 (C6H5), δ 55.6, 55.8, 58.8 (CH2 macrocycle), δ 61 (CH2 amide pendents), δ 63 (CH2 benzyl), and δ 174 (CONH2 amide). [Co(L1)](Cl2). The CoII complex was formed by adding ethanolic solutions (5 mL) of CoCl2·6H2O (0.181g, 0.60 mmol) to ethanolic solution (5 mL) of the ligands (0.142 g, 0.60 mmol). The solution was stirred for at least 1 h, and the precipitate formed after several minutes. The solution was filtered and washed several times with ethanol followed by ether. [Co(L1)](Cl2) 91% yield, pastel blue. ESI-MS: m/z = 181.3 (46%) [M/2]+, 722.3 [2M2H+], 723.3 [2M-H+], 361.2 [M-H]+; 396.8 [M + Cl]+. [Co(L1)](NO3)2, [Co(L2)](NO3)2, and [Co(L4)](NO3)2. To each 10 mL ethanolic solution of L1 (0.025 g, 0.083 mmol), L2 (0.025 g, 0.075 mmol), and L4 (0.041 g, 0.122 mmol) were added 5.0 mL of ethanolic solutions of Co(NO3)2 (0.024 g, 0.082 mmol), (0.022 g, 0.076 mmol), and (0.036 g, 0.124 mmol), and the solutions were stirred overnight. After they were stirred overnight, the volume of these solutions was reduced to 5 mL followed by slow addition of 15 mL of diethyl ether until the complexes precipitated. The complexes were filtered and washed with diethyl ether (10 mL × 3). [Co(L1)]· 2NO3, [Co(L2)]·2NO3, and [Co(L4)]·2NO3 were collected as pink solids with yields of 87%, 80%, and 93%, respectively. ESI-MS of [Co(L1)]2+: 361.2 [M-H]+, 359.2 [M-2H]+, and 181.3 [M/2]+. ESIMS of [Co(L2)]2+: m/z = 197.3 [M/2]+ and 393.2 [M + H]+. ESI-MS of [Co(L4)]2+: m/z = 196.2 [M/2]+, 391.2 [M-H]+, and m/z = 392.2 [M]+. Magnetic Moments. Samples for studies of magnetic moment by using the Evans method were prepared using a coaxial NMR insert that contained the diamagnetic standard of 5% t-butanol in D2O. The outer 5 mm NMR tube contained 5 mM paramagnetic paraCEST complex with fixed concentrations; 4, 8, 40, and 70 mM in the presence of 5% t-butanol. The effective magnetic moment (μeff, BM) was calculated by using a modified Evans method for small molecules at 298 K (T) as described in the Supporting Information.32,82 pH Potentiometric Titrations. Solutions containing 1−1.5 mM Co(II) complex in 100 mM NaCl were titrated with NaOH under Ar at 25 °C. Hyperquad 2013 Version 6.0.1 program was used to determine the protonation states and the pKa values of the complex from the pH data. A speciation diagram was obtained by using the HySS Version 4.0.31 program. CEST Experiments. In general, CEST data were acquired at 37 °C with a presaturation pulse power (B1) of 17.9, 10.0, or 23.5 μT for [Co(L1)]2+, [Co(L2)]2+, and [Co(L4)]2+ complexes, respectively, applied for 2 s at 11.4 T. All samples contained 20 mM 2-(Nmorpholino)ethanesulfonic acid (MES) buffer in 100 mM NaCl. The frequency offset was varied in 500 Hz increments, and a CEST spectrum was obtained by plotting normalized water intensity against frequency offset. Exchange Rate Constants. The exchange rate constants were calculated by using Omega plots.6 Samples contained 8 mM Co(II) complexes, 100 mM NaCl, and 20 mM MES buffers of different pH values. Alternatively, exchange rate constants were calculated by using an HW-QUESP plot.83 The values of proton exchange rates calculated from the two methods are in good agreement (Table S3).

The CEST peak for the [Co(L1)]2+ complex containing three alcohol pendents was highly shifted to 140 ppm versus bulk water. Further efforts are underway to prepare Co(II) complexes with bound water ligands and to tune the rate constant for water exchange toward new paraCEST agents. The variable-temperature 17O NMR studies were performed initially to gain information on the number of bound waters and the water exchange rate constants. These studies showed that it is feasible to form Co(II) macrocyclic complexes with one or two bound waters, although the waters exchange too rapidly to produce a CEST effect. Interestingly, complexes that presumably contain no inner-sphere water also showed evidence of interaction with water by producing a shift and slight broadening of the 17O NMR resonance of water. However, these effects were of smaller magnitude than those of the complexes that had open coordination sites. The Co(II)-induced 1H shifts did not range as widely for the four complexes as did the 17O NMR shifts. In fact, [Co(L1)]2+ and [Co(L2)]2+ had nearly identical slopes, despite the presence of an exchangeable water for [Co(L2)]2+. This shows that hydrogen bonding of the complexes through second-sphere water interactions is effective for complexes with alcohol groups, in particular. This is an important finding, as it suggests that it may not be necessary to have an open coordination site to induce paramagnetic shifts of water 1H resonances. One application for Co(II) complexes that promote a large shift in the proton water resonance is the production of lipoCEST agents. LipoCEST agents contain liposomes that are filled with a paramagnetic shift agent.42 LipoCEST agents reported to date contain Ln(III) complexes, generally Tm(III), Tb(III), or Dy(III).42,79,80 The Ln(III) complex must shift the water proton resonances to as large an extent as possible. In this regard, it is notable that the [Co(L4)]2+ complex shifts the proton resonance of water nearly as well as does one of the best lanthanide shift agents, Tm(DOTA)3+ (Figure S28).44 This promising result bodes well for the development of supramolecular CEST agents based on Co(II) complexes.

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EXPERIMENTAL SECTION

General Instrumentation. CEST data, 1H NMR or 17O NMR spectra, and the Evans method of magnetic susceptibility were obtained on a Varian Inova 500 or 400 MHz NMR spectrometer. All pH measurements were obtained by using either an Orion 8115BNUWP Ross Ultra Semi Micro pH electrode connected to a 702 SM Titrino pH meter. ThermoFinnigan LCQ Advantage IonTrap LC/MS equipped with a Surveyor HPLC system was used to collect mass spectral data. Further details are given in Supporting Information. Synthesis of Ligands. Synthesis of L2. The synthesis of 1,1′-(7benzyl-1,4,7-triazonane-1,4-diyl) bis(propan-2-ol) was adapted from that reported previously.81 In a 10 mL round-bottom flask, 1-benzyl[1,4,7]-triazacyclononane (0.127 g, 0.5795 mmol) was dissolved in 5.0 mL of absolute ethanol. To this solution was added (S)-(−)-propylene oxide (2.9 mmol, 5.0 equiv). After the solution was stirred at room temperature for 24 h the solvent was removed under pressure to yield an oily crude product. The crude product was then dissolved in diethyl ether with gentle heating, and precipitate was removed by filtration. The filtrate was dried under reduced pressure to yield 1,1′-(7-benzyl1,4,7-triazonane-1,4-diyl) bis(propan-2-ol) as a yellow oil (0.1657g, 0.4942 mmol, 85%). Electrospray ionization mass spectrometry (ESIMS): m/z = 336.3 [M + H]+. 1H NMR (400 MHz, CD3OD); δ 1.09 (6H, CH3), δ 2.25−2.94 (12H, CH2 macrocycle and 4H, CH2 alcohol pendents), δ 3.55−3.83 (2H, CH2 benzyl and 2H, CH alcohol pendents) and δ 7.15−7.44 (5H, benzyl). 13C NMR (300 MHz, CDCl3): δ 19.9 (methyl), δ 54.4, 55.2 (macrocycle ring), δ 62.7 (CH2 H

DOI: 10.1021/acs.inorgchem.7b02977 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry 17 O NMR spectra were recorded on a Varian Inova 400 MHz NMR spectrometer equipped with a 5 mm broad-band probe. Peak fitting of the resonances to obtain the half-height at peak maximum was used to calculate the transverse relaxation times of 17O NMR resonances. The Swift−Connick64 equations were used to obtain exchange rate constants for bound water for the Co(II) complexes at pH 6. See Supporting Information for details. X-ray Structure Solution and Refinement. Single-crystal X-ray data of the complexes were collected at 100 K on a Bruker VENTURE Photon-100 CMOS diffractometer at 173 K with APEX 2 software suite. The absorption correction was applied using SADABS,84 the structures were solved by the direct methods using SHELXT,85 and were refined using the SHELXL-2014 program package.86 All nonhydrogen atoms were refined anisotropically; hydrogen atoms were refined with riding coordinates with Uiso = 1.5Uiso(C) for methyl groups and Uiso = 1.2Uiso(N,C,O) in all other cases. Crystallographic data and data collection parameters are given in Table S8.87

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(6) Dixon, W. T.; Ren, J.; Lubag, A. J.; Ratnakar, J.; Vinogradov, E.; Hancu, I.; Lenkinski, R. E.; Sherry, A. D. A concentration-independent method to measure exchange rates in PARACEST agents. Magn. Reson. Med. 2010, 63 (3), 625−32. (7) Liu, G.; Li, Y.; Pagel, M. D. Design and characterization of new irreversible responsive PARACEST MRI contrast agent that detects nitric oxide. Magn. Reson. Med. 2007, 58 (6), 1249−1256. (8) Stevens, T. K.; Milne, M.; Elmehriki, A. A.; Suchy, M.; Bartha, R.; Hudson, R. H. A DOTAM-based paraCEST agent favoring TSAP geometry for enhanced amide proton chemical shift dispersion and temperature sensitivity. Contrast Media Mol. Imaging 2013, 8 (3), 289−92. (9) Hammell, J.; Buttarazzi, L.; Huang, C. H.; Morrow, J. R. Eu(III) complexes as anion-responsive luminescent sensors and paramagnetic chemical exchange saturation transfer agents. Inorg. Chem. 2011, 50 (11), 4857−67. (10) Woods, M.; Woessner, D. E.; Zhao, P.; Pasha, A.; Yang, M.-Y.; Huang, C.-H.; Vasalitiy, O.; Morrow, J. R.; Sherry, A. D. Europium(III) Macrocyclic Complexes with Alcohol Pendant Groups as Chemical Exchange Saturation Transfer Agents. J. Am. Chem. Soc. 2006, 128 (31), 10155−10162. (11) Coman, D.; Kiefer, G. E.; Rothman, D. L.; Sherry, A. D.; Hyder, F. A lanthanide complex with dual biosensing properties: CEST (chemical exchange saturation transfer) and BIRDS (biosensor imaging of redundant deviation in shifts) with europium DOTAtetraglycinate. NMR Biomed. 2011, 24 (10), 1216−25. (12) Li, A. X.; Wojciechowski, F.; Suchy, M.; Jones, C. K.; Hudson, R. H.; Menon, R. S.; Bartha, R. A sensitive PARACEST contrast agent for temperature MRI: Eu3+-DOTAM-glycine (Gly)-phenylalanine (Phe). Magn. Reson. Med. 2008, 59 (2), 374−81. (13) Delli Castelli, D.; Terreno, E.; Aime, S. Yb(III)-HPDO3A: a dual pH- and temperature-responsive CEST agent. Angew. Chem., Int. Ed. 2011, 50 (8), 1798−800. (14) 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. (15) Park, J. G.; Jeon, I.-R.; Harris, T. D. Electronic effects of ligand substitution on spin crossover in a series of diiminoquinonoid-bridged Fe(II)2 complexes. Inorg. Chem. 2015, 54 (1), 359−369. (16) Du, K.; Harris, T. D. A Cu(II)2 Paramagnetic Chemical Exchange Saturation Transfer Contrast Agent Enabled by Magnetic Exchange Coupling. J. Am. Chem. Soc. 2016, 138 (25), 7804−7. (17) 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. (18) De Leon-Rodriguez, L. M.; Viswanathan, S.; Sherry, A. D. Improved synthesis of DOTA tetraamide ligands for lanthanide(III) ions: a tool for increasing the repertoire of potential PARACEST contrast agents for MRI and/or fluorescent sensors. Contrast Media Mol. Imaging 2010, 5 (3), 121−5. (19) Bertini, I.; Luchinat, C.; Parigi, G.; Pierattelli, R. NMR Spectroscopy of Paramagnetic Metalloproteins. ChemBioChem 2005, 6 (9), 1536−1549. (20) Vinogradov, E.; Sherry, A. D.; Lenkinski, R. E. CEST: From basic principles to applications, challenges and opportunities. J. Magn. Reson. 2013, 229 (0), 155−172. (21) 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. (22) 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, 8311. (23) Burns, P. J.; Tsitovich, P. B.; Morrow, J. R. Preparation of a Cobalt(II) Cage: An Undergraduate Laboratory Experiment That Produces a ParaSHIFT Agent for Magnetic Resonance Spectroscopy. J. Chem. Educ. 2016, 93 (6), 1115−1119.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b02977. Experimental details including NMR spectra, CEST spectra, Omega plots to obtain exchange rate constants, and synthetic procedures (PDF) Accession Codes

CCDC 1586385−1586387 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding 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 for support of this work (CHE 1310374 and CHE 1710224). S.M.A. thanks the Egyptian government for a scholarship.

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REFERENCES

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