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A General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry Emily E. Racow, John J. Kreinbihl, Alexia G. Cosby, Yi Yang, Apurva Pandey, Eszter Boros, and Christopher J Johnson J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05874 • Publication Date (Web): 30 Aug 2019 Downloaded from pubs.acs.org on August 30, 2019

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Journal of the American Chemical Society

A General Approach to Direct Measurement of the Hydration State of Coordination Complexes in the Gas Phase: Variable Temperature Mass Spectrometry Emily E. Racow,† John J. Kreinbihl,† Alexia G. Cosby, Yi Yang, Apurva Pandey, Eszter Boros* and Christopher J. Johnson* Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, New York, 11790 ABSTRACT: The formation of ternary aqua complexes of metal-based diagnostics and therapeutics is closely correlated to their in vivo efficacy but approaches to quantify the presence of coordinated water ligands are limited. We introduce a general and highthroughput method for characterizing the hydration state of para- and diamagnetic coordination complexes in the gas phase based on variable-temperature ion trap tandem mass spectrometry. Ternary aqua complexes are directly observed in the mass spectrum and quantified as a function of ion trap temperature. We recover expected periodic trends for hydration across the lanthanides and distinguish complexes with several inner-sphere water ligands by inspection of temperature-dependent speciation curves. We derive gas-phase thermodynamic parameters for discernable inner and second-sphere hydration events, and discuss their application to predict solution-phase behavior. The differences in temperature at which water binds in the inner and outer spheres arise primarily from entropic effects. The broad applicability of this method allows us to estimate the hydration states of Ga, Sc and Zr complexes under active preclinical and clinical study with as-yet undetermined hydration number. Variable-temperature mass spectrometry emerges as a general tool to characterize and quantitate trends in inner-sphere hydration across the periodic table.

INTRODUCTION. The ability to quantify and subsequently tune inner-sphere hydration of coordination complexes is essential for the field of medicinal inorganic chemistry. The hydration state of metalbased compounds for diagnosis and therapy is closely correlated to their efficacy.1-2 Clinically utilized contrast agents for magnetic resonance imaging and some metal-based drugs and metalloenzyme active sites rely on the transient binding of water with defined and optimized dynamics in the inner coordination sphere (Figure 1). Metal-based radiopharmaceuticals that exclude water ligands from the inner coordination sphere can show improved kinetic inertness and luminescent lanthanide complexes benefit from a lack of inner sphere hydration as vibrational excitation of the bound water molecule substantially reduces attainable quantum yields.3-4 In spite of the importance of understanding and modulating innersphere bound water, it is not currently possible to characterize its properties in a range of environments. Commonly used techniques provide no one-stop solution that grants direct access to hydration state and dynamics of all metal ions. Solidstate structural characterization by X-ray crystallography provides only a static snapshot with no thermodynamic information, often not accurately depicting the solute species due to absence of inner- and second-sphere water.5 Synchrotron-based methods such as extended X-ray absorbance fine structure (EXAFS) and X-ray absorption near edge structure (XANES) spectroscopy do not unequivocally distinguish or quantify the number of bound waters.6-7 Pulsed Mims Electron Nuclear Double Resonance (ENDOR) studies have previously been used to estimate the number of bound

Figure 1. Schematic description of inner and outer sphere hydration of a metal complex in solution, where the inner-sphere bound water (red) is bound transiently via a M-O coordinative bond. Second sphere waters (teal) form a hydrogen-bonding network with the ligand, extending to form an outer solvation water shell (light blue).

waters for various paramagnetic coordination complexes.1, 8-11 Nuclear magnetic resonance (NMR) is routinely used to probe the hydration state of metal complexes in solution.12-13 17OH2 variable temperature nuclear magnetic resonance measurements can inform on quantity (referred to as q) and exchange rates of metal-ion bound water under certain circumstances.14-15 Other methods of estimating inner-sphere hydration are similarly restrictive: The lifetime of metal-based luminescence can be employed to approximate the number of water molecules present within the inner coordination sphere; however, this method is only applicable to lanthanides.16-19 Furthermore, lanthanide luminescence is sensitive to vibrational de-excitation by ligand N-H and O-H oscillators, producing numerical results for inner-sphere hydration that can

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incur a standard error of as low as 10% even after application of empirically determined correction factors.20-21 The inner-sphere hydration of coordination complexes directly affects their biological behavior. 44Sc(III), 68Ga(III), 177 Lu(III) and 89Zr(IV)-coordination complexes are currently undergoing preclinical and clinical trials as positron emission tomography (PET) tracers and targeted radiotherapeutics for cancer.22-24 In some cases, in vivo studies indicated that coordination complexes with water ligands present in the inner sphere can exhibit diminished complex inertness. While coordination complexes with pronounced inner sphere hydration (q=1,2) can exhibit high stability and kinetic inertness,25-26 displacement of inner sphere water ligands appears to promote complex dissociation in 89Zr(IV)-labeled biologics with multi-day in vivo circulation times and may limit the diagnostic potential of these PET tracers.27-28 Similarly, indium and lutetium complexes can exhibit accelerated complex dissociation when complexed with hexadentate chelators which allow for coordination of 1-2 waters or competing ligands.29-30 Elucidation of the solution structure of these complexes is essential, but the hydration status of Zr(IV) complexes remains inaccessible experimentally. To improve and streamline the molecular design of improved medicinal inorganic chemistry complexes, we sought methods that enable quantitation of inner-sphere hydration of systems like Zr(IV) complexes and other dia- and paramagnetic metal ions where the number of inner-sphere water ligands is not readily experimentally available. Mass spectrometry using cryogenically-cooled ion traps enables the formation and detection of molecular adduct complexes,31 and variable temperature ion traps allow the evaluation of binding energetics by thermal decomposition.32-35 We hypothesized that the combination of these approaches could be used to quantify the hydration status of ternary complexes independently of the identity of the metal center by direct mass spectrometric observation of the hydrated species in the gas phase. We argued that 1) low temperatures in an ion trap will sufficiently slow the binding kinetics to observe the ternary complex and 2) the coordination of a water molecule in the inner-sphere will have a unique thermodynamic character to that of the ligand, and will occur at a distinct, higher temperature than more loosely bound second-sphere waters due to the differences in their binding motifs. This method is essentially the reverse of thermogravimetric analysis (TGA), except performed in the gas rather than solid phase and with the ionizable sample composition innately known via mass spectrometry. As such, it is independent of counter ions or impurities, requires nanomoles of sample, and is not dependent on water being bound in the solid phase. These factors combine to make standard TGA methods often unreliable to determine the structural location of water.36 Example TGA experiments for two complexes studied here is shown in the Supplementary Information. Here, we first confirm that this approach correctly reflects the solution-phase hydration of complexes of well-studied ligands with lanthanides and first row transition metals, identifying the behavior of inner- and second-sphere water. Next, we determine the gas-phase hydration state of Zr, Ga, and Sc-complexes that are clinically relevant but difficult to access using typical analytical approaches. We then quantify the gas-phase water binding thermodynamics across this range of metals and ligands, extracting trends in enthalpic and entropic

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contributions to the free energy of water binding. We use this information to suggest thermodynamic limits that can be used to classify the water binding sites for these complexes as inneror outer-sphere and suggest routes for development of ligands with improved performance for biomedical applications. Finally, we discuss the limitations and a failure of this technique and recommend best practices. EXPERIMENTAL SECTION Synthesis of coordination complexes. Complexation of all ligands was completed by dissolving the corresponding ligand and lanthanide salt in water at a 1:1 ratio under acidic conditions, following previously published procedures and as outlined in the Supporting Information. The pH of the mixtures was adjusted to 7.0 by addition of 0.1 M NaOH. The resulting suspensions were centrifuged to remove any precipitating lanthanide salts. The supernatants were collected and lyophilized overnight, yielding the complex products as a white solid without any further purification. Variable Temperature Mass Spectrometry. All variabletemperature mass spectrometry (VT-MS) experiments were carried out on a quadrupole time-of-flight mass spectrometer outfitted with a cryogenic ion trap. Ions were generated in an electrospray ionization (ESI) source purged with dry nitrogen, via a fused silica emitter pulled to 30 μm inner diameter. Solutions of complexes diluted to 1-100 μM in methanol or 50% acetonitrile in methanol were introduced via a syringe pump at 0.4-0.7 μL/min, and ESI voltages were held just above the threshold for spraying in order to minimize sample degradation. Ions were transported into a vacuum system and stored in a room temperature octopole ion trap. At a rate of 10 Hz, ions were ejected from this trap and the desolvated complex was mass selected by a quadrupole mass filter. Complexes of interest were then guided to another octopole ion trap attached to a cryogenic cold head capable of operation down to 3 K. The ion trap was cooled from 310 K (320 K if hydration was noted at 310 K) at ~1 K/min as measured by a Si diode attached to the trap assembly. Here, a mixture of ~0.1% by pressure H2O seeded in helium was introduced via a pulsed valve into the trap, where it quickly thermalized to the trap temperature. If thermodynamically favorable, hydrated complexes formed in this trap. A fraction of the ions were extracted from this ion trap into a reflectron time of flight mass spectrometer at a 10 Hz rate approximately 80 ms after the pulse, yielding an average residence time of ~1 second for ions in the trap. This allowed time for the hydrate distribution to reach steady state, and lower duty cycles yield the same hydrate distribution. Mass spectra consisting of an average of 1000 cycles were recorded at 10 K intervals during the cooling period. The partial pressure of water in the vacuum chamber was monitored by a residual gas analyzer, and typically varied from 1x10-7 to 4x10-8 torr as a function of cold head temperature. Each experiment was carried out at least in duplicate to determine reproducibility of the results. Data processing and analysis. Mass spectra were baselinecorrected and normalized to the most abundant isotope of the complex. The dominant isotope of each hydrate was individually integrated to yield the relative hydrate populations. This approach was necessary to avoid overlaps of isotope distributions, particularly in the case of Gd. The relative


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intensities of each hydrate as a function of temperature were tabulated for presentation as speciation curves or for further thermodynamic analysis as described below. RESULTS AND DISCUSSION. Validation of Lanthanide Complexes. To probe our hypothesis that inner sphere water ligands will bind at higher temperature than second sphere water, we selected metal complexes with well-characterized hydration numbers such as coordination complexes of the lanthanide series (q = 1,0). Neutron diffraction, XANES and Pulsed Mims Electron Nuclear Double Resonance (ENDOR) studies have previously been used to estimate the number of bound waters for Gd(III) coordination complexes.8 Eu(III), Tb(III), Nd(III), Dy(III) inner-sphere hydration is directly proportional to the difference of fluorescent decay rates measured in H2O and D2O as the OH oscillator of inner-sphere bound water efficiently quenches lanthanide luminescence.19 Systematic 1H-NMR studies on 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetate Lanthanide, [Ln(DOTA)]- complexes across the entire lanthanide series and the pseudolanthanide Sc(III) have been utilized to identify conformational and coordination equilibria and approximate q.37 Hydrated and non-hydrated complex species exhibit structural isomerism that further complicates spectroscopic assignments of 1H-NMR shifts, complicating the characterization of more complex, functionalized systems.37 As a first proof of concept, we selected the 8-coordinate ligand DOTA and the 9-coordinate ligand 2,2’,2”-(10-((6carboxypyridin-2-yl)methyl)-1,4,7,10-tetraazacyclo-dodecane1,4,7-triyl)triacetic acid (DO3Apic) to form complexes with five trivalent ions across the lanthanide series: La(III), Eu(III),

Figure 2. Coordination complexes with known hydration state studied in this manuscript. Ln = La, Eu, Gd, Tb, Lu.

Gd(III) , Tb(III) Lu(III) as shown in Figure 2. We hypothesized that VT-MS would affirm DOTA as q=1 for large lanthanides and q=0 for small lanthanides,37 while DO3Apic would consistently form q=0 complexes with all metal ions investigated. In our discussions, we will refer to n to identify a given water adduct number irrespective of hydration sphere, while q will refer specifically to the number of water ligands directly bound to the metal ion or inner coordination sphere, as is customary. A representative set of mass spectra comparing the hydration behavior of [Gd(DOTA)]- (clinically used as Dotarem) with that of [Gd(DO3Apic)]- is shown in Figure 3, left. At the highest temperature shown, both complexes existed purely in the unhydrated state n=0 in the trap (black trace), as evidenced by the lack of other peaks appearing in the mass spectrum. Since the unhydrated complex was specifically isolated in the quadrupole mass filter before the ion trap, this shows that at elevated temperature, no water is able to bind to the complex. As the temperature was lowered, the mass spectrum for the DOTA complex showed the gradual appearance of another set

Figure 3. (Left) Variable-temperature mass spectra of hydrated [Gd(DOTA)]– (black) and [Gd(DO3Apic)]–- (gray, inverted). As the masses of the two ligands differ, the mass spectra are plotted in terms of the difference in mass from the dry complex to aid comparison. Nearly complete conversion to the singly hydrated DOTA complex occurs at 210 K, while the DO3Apic complex only exhibits nonspecific second sphere hydration beginning below 190 K. Complexes of same n are indicated by colored boxes that correspond to speciation plot assignments. * denotes a minor acetic acid adduct species, only observed for [Gd(DOTA)]–. (Right) Derived speciation curves from the two VT-MS series showing clear quantitative differences for the first water. The gray box denotes the empirically determined temperature zone of characteristic inner-sphere hydration.



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Figure 4. (Left) Speciation curves for [Ln(DOTA)]- complexes, where Ln = La, Eu, Gd, Tb, and Lu. As expected, La shows inner-sphere hydration at the highest temperature, while Eu, Gd, and Tb singly hydrate at progressively lower temperatures. Lu shows hydration behavior comparable with and characteristic to all DO3Apic complexes (right).

of peaks with an identical isotope pattern 18 amu higher, which we ascribe to the coexistence of unhydrated and singly hydrated peaks (n=1, pink trace) in the ion trap. The onset of water binding was 240 K, with essentially complete conversion into the singly hydrated n=1 species by 200 K. However, the DO3Apic complex remained unhydrated until 190 K. Both species display similar broad hydrate distributions at lower temperature that we ascribed to second-sphere water (all other representative colored traces). Thus, the mass spectrum provides direct observation of the gas-phase hydrate distribution, at any given temperature, but does not provide structural assignments for each water. An acetic acid adduct was also present in the mass spectra but, given that there are no mass coincidences with the hydrates, it did not affect these results. Even from qualitative analysis of the mass spectra, it is clear that [Gd(DOTA)]– features one unique water molecule that binds at a substantially higher temperature than does [Gd(DO3Apic)]–. However, further analysis made this contrast clearer. Shown in Figure 3, right are temperature-dependent speciation curves for the hydrates. As expected, at high temperatures only the n=0 species was observed, while at lower temperatures, hydrates were observed. A notable difference is apparent between the two complexes, with a broad curve for the n=1 hydrate peaked at 210 K for [Gd(DOTA)]-, for which there is no corresponding signal in the speciation curves of [Gd(DO3Apic)]-. Both complexes show a dense set of sequential hydration curves below 200 K, which we have assigned to the onset of second-sphere water, specifically water binding to the ligand via transient hydrogen bonding interactions.38 Given the correspondence between the appearance of the n=1 hydrate at high temperature and the expectation that [Gd(DOTA)]– should bind an inner sphere water, we conclude that the n=1 signal for [Gd(DOTA)]- is indeed the formation of a q=1 complex in the ion trap. The n=1 signal for [Gd(DO3Apic)]- arises from water binding to the ligand in the second sphere, as is expected for this nominally q=0 complex. Further support for this argument is the strong

similarity between the n=2 curve for [Gd(DOTA)]– and the n=1 curve for [Gd(DO3Apic)]–, suggesting that these two water molecules occupy similar binding sites on the ligand. It is expected that the binding affinity of inner-sphere water should follow the periodic trend for ionic radius in lanthanides, as the size of the binding pocket decreases with decreasing radius of the trivalent metal ion. Figure 4 compares the speciation curves for selected [Ln(DOTA)]– complexes spanning the lanthanide series. DOTA complexes of La, Eu, Gd, Tb with a known q=1 showed the formation of a singlyhydrated complex at temperatures as high as 260 K, followed by formation of an observable secondary hydration sphere below 200 K. The formation of the n=1 species of the corresponding DO3Apic complexes occurred at lower temperatures, and these complexes show essentially identical speciation curves that similarly indicate q=0 for all metal ions studied here (Figure 4). Notably, DOTA and DO3Apic complexes of Lu(III), exhibit identical hydration speciation behavior, indicating that formation of the predominantly singly hydrated species did not occur. VT-MS plots comparing ligands for all complexes are also given in the supplementary information. The lack of a clear signature of an inner-sphere water for both Lu complexes is in agreement with previous, NMR-based studies that indicate that a q=0 for both [Lu(DOTA)]- and [Sc(DOTA)]- complexes is likely the most thermodynamically favored species.37 From these observations, we define a region of temperature, shown shaded in all plots in this manuscript, in which peaks associated with inner sphere waters appear to lie. These observations show that, while mass spectrometry is incapable of identifying a metal-oxygen coordination bond, qualitative analysis of the mass spectra as a function of temperature yields direct insight into the hydration number of the complexes under these MS conditions. The close correspondence between the gas-phase and solution-phase behavior of this set of complexes, and the reproduction of periodic trends, suggest that VT-MS results may provide insight


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Figure 6. Zirconium coordination complexes with unknown hydration state studied in this work. q estimates are based on computational studies. The corresponding gallium(III) complexes are q=0.

Figure 5. Speciation curves for [Lu(EDTA)]–- and [Sc(EDTA)]–. The two complexes show analogous but also distinct hydration, identifying key differences between inner-sphere hydration of the two complexes.

into solution-phase behavior. Thus, we expanded the scope of our study to include complexes with different q values to determine the specificity of the technique. Bishydrated complex species. To access species with more inner sphere waters, we formed complexes with the hexacoordinate ligand ethylene diamine tetraacetate (EDTA) and metal ions with preference for 8- and 9-coordinate complex formation, in this case Sc(III) and Lu(III). Solid-state X-ray structures characterize both [Lu(EDTA)]- and [Sc(EDTA)]- as 8-coordinate with two inner sphere water ligands, but the different ionic radii result in at least 0.1 Å differences in the MO and M-N bond lengths in the respective solid state structures.39-40 We sought to confirm these structures with VTMS. As shown in Figure 5, both complexes showed characteristic inner-sphere hydration. Despite the fact that only unhydrated complexes pass through the quadrupole mass filter, [Lu(EDTA)]- exists in equilibrium between unhydrated and

singly hydrated forms in the ion trap even above room temperature. For [Sc(EDTA)]-, the onset of hydration occurred at slightly lower temperatures and only two water molecules with inner sphere character are observed with the third water comparing well to characteristic second sphere hydration as shown by q=0 complexes of the investigated lanthanide series. It thus appears that [Sc(EDTA)]- and [Lu(EDTA)]- can be identified as bishydrated or q=2, though [Lu(EDTA)]- displays a particularly strong n=3 peak and the first hydrate appears at higher temperature. Based on the criteria derived for the DOTA/DO3Apic complexes, the hydration state of this complex could be 2 or 3. Its exact assignment can be determined by its derived binding thermodynamics as discussed further below. Characterizing Zr complexes with unknown hydration status. VT-MS appears to reliably approximate hydration numbers in the gas phase for complexes with known hydration status determined in solution for inner-sphere hydration ranging from q=0 to q=2. We next sought to characterize coordination complexes for which quantitation of hydration state is not experimentally accessible. The aqueous coordination chemistry of Zr(IV) is underexplored to date in spite of the increasing relevance of 89Zr for PET imaging. The complexation of 89 Zr(IV) is achieved by Fe(III)-siderophore-antibody conjugates.41 The difference in size and charge in comparison

Figure 7. Speciation curves for DFO and LDFC complexes with Ga and Zr. Shaded in gray is the region in which inner-sphere hydration is expected to occur. [Zr(DFOH)]2+ shows single hydration even above room temperature, while Ga does not. For the related LDFC ligand, Zr hydration shows an atypical shape for the first hydrate.



to Fe(III) is hypothesized to produce Zr(IV) siderophore complexes that allow coordination of one or two inner-sphere water ligands,42-43 lowering the relative kinetic inertness of the corresponding Zr(IV) coordination complex with hexacoordinate ligands and leading to diminished in vivo complex stability. We chose two coordination complexes of Zr(IV) for which computational studies have investigated ternary complex formation to rationalize their diminished in vivo kinetic inertness: the hexacoordinate ligands desferrioxamine (DFO)33 and linearized desferrichrome (LDFC)34. These ligands form the coordination complexes [Zr(DFO)(H2O)q]+ and [Zr(LDFC)(H2O)q]+ (Figure 6). Optimization of the coordination environment in the gas phase with the B3LYP hybrid functional indicated q=2 for the [Zr(DFO)(H2O)2]+ complex, while calculations on [Zr(LDFC)(H2O)q]+ indicated that the complex is present predominantly as q=1.44-45 As q=0 references, the corresponding hexacoordinate [Ga(DFO)] and [Ga(LDFC)] complexes were also synthesized. VT-MS results for [Zr(DFOH)(H2O)n]2+ show an equilibrium between q=0 and 1 near room temperature, indicating the presence of at least one very strongly bound inner-sphere water. Lower temperatures did not lead to formation of q=2 complexes, but rather the formation of a characteristic secondsphere hydration below 200 K (Figure 7). As expected, the corresponding Ga complex did not show notable inner-sphere hydration and is assigned as q=0. [Zr(LDFC)(H2O)n]+ exhibits formation of q=1 at lower temperatures with a uniquely bimodal distribution, indicating that this structure accommodates innersphere water to a lesser extent than the [Zr(DFO)(H2O)n]+. This result shows a similar order for hydration propensity as DFT calculations predicted q=2 for [Zr(DFO)(H2O)n]+ and q=1 for [Zr(LDFC)(H2O)n]+, but lower over-all net hydration.44-45 The bimodal nature of the n=1 curve for [Zr(LDFC)(H2O)n]+ is consistent with a minor isomer with higher water affinity and a major isomer with somewhat lower affinity for binding of an inner-sphere water molecule. Both [Zr(LDFC)(H2O)n]+ species observed appear to be q=1 complexes. This indicates that zirconium(IV) complexes likely form heptacoordinate, ternary coordination complexes, comprised of chelation by the hexadentate siderophore and coordination of a single innersphere water. This has consequences for future ligand design considerations, as efforts to date have focused on the development of octadentate coordination environments for Zr(IV), whereas heptadentate, siderophore-derived chelators may also efficiently exclude inner-sphere water. Taken together, these results demonstrate that the inner-sphere hydration of a thus far inaccessible metal complex species can be characterized, at least in the gas phase, using VT-MS. Finally, we note that [Ga(LDFCH)]+ displays a strong signal for n=4, such that this is the dominant hydrate below 190 K. We tentatively assign this to the formation of a particularly stable hydration structure upon the binding of the fourth water. This is analogous to the so-called shell closings often found in atomic and molecular clusters, in which a given cluster is much more stable than the next larger cluster. We hypothesize that [Ga(LDFC)]+ exhibits a structure that is conducive to the construction of a hydration shell in which four molecules are found in ideal hydrogen bonding geometries, while the fifth water can find no similarly ideal binding site and thus its evaporation rate is substantially higher.

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Figure 8. (Top) The van ‘t Hoff plot for all DOTA and DO3Apic complexes, with the regions corresponding to inner- and outer-sphere water shaded yellow and blue, respectively. (Middle) Plot of experimentally derived ΔG298 values for the first water on select complexes. (Bottom) Plot of experimentally derived ΔG298 values for the second water on the same complexes. These plots show a distinct difference in behavior for the q=2 [Lu(EDTA)]– complex than the q=1 [Zr(DFOH)]2+ complex.

Thermodynamics of hydration. While the qualitative analysis described above permits rough separation of hydration states, it does not provide clear guidelines for borderline cases. We determined the gas phase enthalpies, entropies, and free energies of hydration for each hydrate, with the goal of establishing ranges in these parameters for inner- and outersphere hydration that best reflect solution phase behavior. Speciation curves allow the derivation of equilibrium constants for the nth water adduct at each temperature, which we compute by 𝐾" =

'

()* % ∑&+, &

-./ 0 ∙∑234 &+5 %&

(Eq. 1)

where Ii denotes the relative integrated intensity of the complex with i bound waters and pH2O is the partial pressure of water at that temperature in atm.32 This equilibrium constant does not


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suggest full thermodynamic equilibrium, as the temperature of trapped ions is still a matter of some uncertainty46 and the experiment is not performed at constant pressure, but rather that the hydrate distributions have reached steady state. From the derived equilibrium constants we generated a van ‘t Hoff plot as shown in the top of Figure 8. It is immediately apparent that q=0 and q=1 complexes can be grouped on this plot, with q=0 complexes nearly overlaid and q=1 complexes dispersed to the upper left in an order corresponding to the ionic radius of the metal ion. From these observations, we defined zones of the van ‘t Hoff plot that correspond to finding water in the inner (blue, in Figure 8) and outer (yellow, in Figure 8) sphere.

Consistent with the qualitative analysis of the speciation curves, the [Lu(DOTA)]– curve is indistinguishable from any DO3Apic complex, further confirming the q=0 assignment. Efforts towards quantitatively linking these values to their solution phase analogues are ongoing. What is clear is that the extent to which a q=1 species differs from the q=0 complex denotes the relative favorability of the inner-sphere binding site over those in the solvation shell, with the La-Lu curves bracketing this range for the lanthanide series. It is also possible to calculate the Gibbs free energy of individual hydration steps at any temperature of interest. Shown

Table 1. Summary of ΔH, ΔS and calculated ΔG298(kJ/mol) values for binding of the inner- and first second sphere waters for complex series investigated and determined by VT-MS. High T and Low T refer to the components of the [Zr(LDFC)]+ first water speciation curve corresponding to higher and lower temperature binding, respectively.

Compound

ΔH (kJ/mol)

ΔS (J/mol•K)

ΔG298(kJ/mol)

Assigned q value

st

-53.8 ± 2.2

-29.6 ± 9.5

-44.8 ± 3.6

1

st

-54.7 ± 0.6

-44.2 ± 2.9

-41.5 ± 1.1

1

st

-62.8 ± 0.9

-80.5 ± 3.8

-38.8 ± 1.4

1

st

-59.3 ± 0.7

-73.9 ± 3.1

-37.2 ± 1.2

1

st

-60.9 ± 3.4

-120 ± 18

-25.2 ± 6.4

0

st

-61.7 ± 4.1

-110 ± 21

-30.2 ± 7.7

1

st

-59.2 ± 4.2

-98 ± 21

-30.2 ± 7.7

1

st

-66.2 ± 8.3

-140 ± 43

-26 ± 15

1

st

Hydration event −

[La(DOTA)]

1 inner-sphere

−

[Eu(DOTA)]

1 inner-sphere

−

[Gd(DOTA)]

1 inner-sphere

−

[Tb(DOTA)]

1 inner-sphere

−

[Lu(DOTA)]

1 second-sphere

−

[La(DOTA)]

1 second-sphere

−

[Eu(DOTA)]

1 second-sphere

−

[Gd(DOTA)]

1 second-sphere

−

[Tb(DOTA)]

1 second-sphere

-67.4 ± 5.7

-140 ± 30

-25 ± 10

1

[Lu(DOTA)]−

2nd second-sphere

-64.0 ± 3.2

-160 ± 18

-16.0 ± 6.2

0

[La(DO3Apic)]−

1st second-sphere

−

[Eu(DO3Apic)]

-62.2 ± 6.1

-140 ± 32

-22 ± 11

0

st

-62.4 ± 4.2

-110 ± 21

-28.3 ± 7.5

0

st

-60.2 ± 6.1

-120 ± 32

-30 ± 11

0

st

-62 ± 4

-130 ± 21

-24 ± 7.5

0

st

-63.1 ± 2.6

-130 ± 14

-23.4 ± 4.8

0

st

-64.6 ± 1.8

-65.7 ± 7.4

-45.1 ± 2.9

2

st

-64.8 ± 1.4 -64.9 ± 2.4

-27.3 ± 4.8 -83 ± 10

-57 ± 2 -40.2 ± 3.9

2

st

nd

-58.6 ± 0.6

-78.5 ± 2.7

-35 ± 1

2

nd

1 second-sphere

−

[Gd(DO3Apic)]

−

[Tb(DO3Apic)]

1 second-sphere 1 second-sphere

−

[Lu(DO3Apic)]

1 second-sphere

−

[Sc(EDTA)]

1 inner-sphere

−

[Lu(EDTA)]

1 inner-sphere −

[Mn(II)(EDTA)] −

[Sc(EDTA)]

1 inner-sphere 2 inner-sphere

−

1

[Lu(EDTA)]

2 inner-sphere

-58.1 ± 1.7

-60.0 ± 7.3

-40.1 ± 2.7

2

[Sc(EDTA)]−

1st second-sphere

−

[Lu(EDTA)]

-57.1 ± 0.4

-107.0 ± 2.4

-25.3 ± 0.8

2

st

-59.6 ± 1.7

-96.8 ± 8.6

-31 ± 3

2

st

1 second-sphere −

[Mn(II)(EDTA)]

1 second-sphere

-69.1 ± 2.0

-119.4 ± 2.1

-33.7 ± 3.3

1

[Zr(DFOH)]2+

1st inner-sphere

-69.7 ± 2.6

-45.0 ± 9.1

-56.3 ± 3.8

1

[Zr(LDFC)]+ (High T)

1st inner-sphere

-36.8 ± 1.1

-32.6 ± 4.1

-46.5 ± 1.6

1

[Zr(LDFC)]+ (Low T)

1st inner-sphere

-43.4 ± 0.8

-4.7 ± 3.7

-42.0 ± 1.3

1

[Zr(DFOH)]2+

1st second-sphere

-54.0 ± 5.8

-94 ± 32

-27 ± 10

1

[Zr(LDFC)]+

1st second-sphere

-43.1 ± 3.6

-33 ± 19

-32.8 ± 6.8

1



in Figure 8 are plots of experimentally derived ΔG values as a function of temperature, as determined by Δ𝐺 = −𝑅𝑇 ln 𝐾" (Eq. 2) Fits to these curves can be extrapolated to 298 K, yielding room temperature ΔG values that we denote ΔG298. We summarize these values for all complexes in Table 1 and include the calculated ΔG298 value. As in the van ‘t Hoff plots, we can clearly distinguish the binding event of an inner-sphere water from the formation of a second-sphere hydrate by characteristic ΔG298 and ΔS values, as denoted again by blue and yellow shading, respectively. As expected, linear fits of these plots yielded values of ΔH and ΔS that very closely match those derived from the van ‘t Hoff plot. No strong trend emerges connecting enthalpy to hydration state, with all values of ΔH lying in the range of -50 to -70 kJ/mol, regardless of water binding site for DOTA, DO3Apic, EDTA, and DFO ligands. For the LDFC ligand, Zr complexes show more complicated behavior and lower binding enthalpies. However, discrimination between sites is found in the changes in free energy and entropy upon binding. Given the behavior of the known DOTA and DO3Apic ligands, we conclude that formation of an M-O bond is a thermodynamically more favorable binding event with ΔG298 values ranging from -60 to -34 kJ/mol with an entropic value ΔS of -5 to -80 J/mol•K. Second-sphere hydration is thermodynamically less favored, with ΔG298 values ranging from -34 to 0 kJ/mol for these ligands. The corresponding ΔS ranges from -80 to -140 J/mol•K, indicating that second-sphere water binding events incur a greater entropic penalty. From these observations, we conclude that ΔG298 displays the strongest discrimination between inner- and second-sphere hydration as compared to ΔH or ΔS. The observation that the magnitude of the change in entropy upon water binding is larger for second-sphere water than innersphere at first seems counterintuitive. We hypothesize that formation of hydrogen-bonding interactions with both hydrogens of a second-sphere bound water more efficiently restricts degrees of motion, while formation of the M-O bond in the inner-sphere is less restrictive, as the metal- ion bound water retains rotational freedom around the M-O axis (Figure 9). The rough increase of the magnitude of ΔS values as the size of the lanthanide ion decreases in the [Ln(DOTA)]- series and is in accordance with increasingly restricted movement of the bound water within the shrinking inner-sphere water binding pocket. It appears that water binding within the ion trap is therefore strongly driven by binding entropy – a parameter thus far not straightforwardly experimentally accessible and complementary to kinetic considerations of water exchange derived using NMR methods in solution which reveal entropic and enthalpic parameters of the dynamic water exchange process.13 Importantly, approximate ranges for ΔG298 of inner- versus second-sphere hydration remain comparable across different species investigated. For EDTA complexes, each hydration event incurs essentially the same enthalpic change, but hydration of Lu shows a smaller magnitude change in entropy compared to Sc. This is easily understood as arising from the larger ionic radius of Lu(III) compared to Sc(III). Binding of a third water to these nominally q=2 complexes occurs with a ΔG298 of -25.3 kJ/mol for Sc, signifying second-sphere binding, but at -31 kJ/mol for Lu, at the border between inner- and

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Figure 9. Schematic description of the restriction of degrees of freedom upon binding of water in the inner- and second sphere and corresponding free energy value range measured.

second-sphere binding. Taken together, these results suggest that [Lu(EDTA)]– also exists predominantly as the q=2 species. The transition-metal Zr(IV) complexes show complex behavior. The inner-sphere water for [Zr(DFOH)]2+ is bound by -56.3 kJ/mol, while the second bound water (-27 kJ/mol) falls in line with second-sphere bound waters. In the case of [Zr(LDFC)]+, two independent linear regions are found in the van ‘t Hoff plot for the first water. Independent fitting of these regions yield one fraction with ΔG298 = -46.5 and another of 42.0 kJ/mol. We hypothesized earlier in this manuscript that two different isomers gave rise to this unique behavior. At lower temperature, where one isomer can be expected to dominate, a ΔS of -32.6 J/mol•K indicates that the binding site of the first water is relatively more restrictive in the high temperature isomer than the low temperature isomer (ΔS = -4.7). At higher temperatures, where we expect a mixture of isomers, the magnitude of ΔS drops significantly, as expected. For either ligand, the second bound water shows very similar binding thermodynamics with ΔG298 values strikingly similar to those of the first second-sphere water bound to the DOTA complexes. Thus, we confirm our assignment above from inspection of the speciation curves that Zr complexes show q=1, though the details of the inner-sphere water binding appear to be quite different. The analogous Ga complexes do not show appreciable water binding and thus are not amenable to this thermodynamic analysis. Scope and Limitations. VT-MS serves as a general tool to estimate inner-sphere hydration of coordination complexes, and can be used when established solution-phase techniques cannot be applied. Here we will discuss the limitations of the conclusions that can be drawn from VT-MS experiments about solution phase behavior, and how we expect it to be best applied. The fact that the experiment is carried out identically across p-, d-, and f-block metal ions permits comparisons of the trends in behavior of a wide range of complexes in a way that is difficult with metal-specific detection schemes. The technique is not limited by magnetic properties, spin of the corresponding metal center or water exchange rate and thus applicable to any charged metal complex. We have shown that coordination complexes of transition metals, metalloids and lanthanides are suitable for analysis using this method, providing complementary information to computational and solid state approaches when NMR and luminescence-based techniques are inapplicable. We predict that VT-MS is well suited to characterize the hydration status of weakly bound


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alkali-, earthalkali- and actinide ions to complement XANES studies and access information on extremely labile, rapidly exchanging water molecules or characterize samples which are only available in highly dilute concentrations. However, this approach has several practical limitations. As a mass spectrometry-based technique, VT-MS requires the generation of charged complexes, requiring the analyte to exhibit intrinsic charge or Bronsted acid/base character. Additionally, as the analysis done here requires allowing the hydrate distribution to reach steady state, it was not possible to determine kinetic rates of water exchange of interest for MRI contrast agent development. Given that these exchange rates underlie the steady state distributions observed, it is possible that they will be accessible after careful calibration. Though not currently widely available, as the instrumentation used is custom built, efforts to adapt this technique to commercial quadrupole time-of-flight mass spectrometers are ongoing. The experimental cycle is limited by the cool-down time of the cold head, which in this case is approximately 50 minutes but could be halved with a faster-cooling apparatus. However, multiple samples could be run in parallel at each temperature point, which would not notably increase the length of the experiment but would substantially increase the throughput. The key question is whether the information gained in these studies is directly applicable to the solution-phase behavior of these complexes. Data can be acquired on any ionizable complex, but verification that the geometric and electronic structure of the complex in the gas phase reflects that of the solution phase is beyond the scope of this technique. As a specific example of an instance in which the gas phase behavior differs from that in the solution phase, [Fe(III)(EDTA)]– is known to be q=1 by NMR methods47 but shows clear q=0 character with this method (see Figure S22). We hypothesize that this results from spin crossover to the smaller-ionic-radius low-spin state of iron, effectively closing the binding site on the Fe ion. Similar spin crossovers for Fe(III) complexes that are high spin in solution have been observed to result from a loss of hydrogen bonding interactions in both the gas and solid phases.48-49 This condition is most likely found for first row transition metals, but we have confirmed the expected results for Sc (q=2),39 Mn(II) (q=1),50 Mn(III) (q=0),51 and Ga(III) (q=0),52 suggesting this is uncommon. EDTA complexes that show q=0 character lack second-sphere hydration, thus thermodynamic parameters cannot be extracted. We speculate that this lack of hydration is a consequence of small structural differences in the binding of EDTA ligands compared to DOTA/DO3Apic, weakening the bidentate hydrogen bonding for second-sphere water. In contrast, Mn(II) is assigned q=1 based on the ΔG298 values for the first (-40.2 ± 3.9 kJ/mol) and the second hydration event (-33.7 ± 3.3 kJ/mol), albeit the second hydration event lies on the border of what can be considered inner- or second-sphere hydration under these gasphase conditions. This observation warrants caution for results of any single complex, but the broad applicability of this technique allows trends with respect to changes of metal ion or ligand to be tracked, improving the chances of detecting outliers. Such structural transformations upon introduction to the gas phase can be reliably diagnosed using ion mobility mass spectrometry to determine the collision cross-section of the gasphase complex as compared to that predicted by molecular dynamics simulations.53 This additional information, which can be obtained using increasingly common commercial

instrumentation, will substantially improve the predictive capability of this technique. However, for first row transition metal ions in which these transformations are likely, wellestablished NMR methods already exist, and thus the benefit of using VT-MS is minimal. Furthermore, VT-MS provides quantitative results on water binding thermodynamics in the gas phase. While the exact thermodynamics of water binding will certainly be different in solution than the gas phase, we do not expect the relative trends to change or the energetic ordering of complexes to shift. In this way, it is no different than quantum chemical studies that are typically performed in gas phase or continuum solvation environments, neglecting specific solvent interactions for water in direct contact with the ligand. As the objective of this approach is to evaluate the access of water to metal ions in these complexes, rather than quantifying solution-phase binding energies, the thermodynamic values presented here should not be assumed to reflect those in solution. Perhaps coincidentally, they are quite similar to those typically found for similar complexes in solution, and the construction of an appropriate thermodynamic cycle, including free energies of solvation of unhydrated and hydrated complexes, could provide a good estimate of the solution-phase energetics. Work is ongoing in our laboratories to establish a protocol to make this connection. At the current time, this technique at least appears to reliably indicate the hydration number of these complexes. CONCLUSIONS We have shown that tandem mass spectrometry coupled to a variable temperature ion trap can be used to characterize the gas-phase hydration status of a range of coordination complexes with relevance in biomedical applications. This analytical method directly determines hydration state of para- and diamagnetic ternary coordination complexes in the gas phase, regardless of oxidation state. From the temperature dependence of the hydrate distribution, we deduced the population of water molecules, q, bound in the inner sphere and the thermodynamics of complex hydration. Given that the structure and electronic states of the solution-phase complexes are maintained in the gas phase, this technique appears to provide a reliable estimation of the solution-phase hydration of these complexes. We note an example failure for an Fe(III) complex and suggest approaches to probe its veracity. As it is not dependent on the identity of the metal ion, this approach can be used to explore trends across metal ion and ligand series. This experimental approach can be adapted to commercial tandem mass spectrometers. We expect this technique to be of particular use for examining trends in hydration, rapidly screening new complexes, and estimating hydration for complexes for which no other analytical tool is feasible, but it does not supersede highly accurate solutionphase methods when they are applicable. Potential applications of this technique extend far beyond the scope of medicinal inorganic chemistry to characterization of bi-, hetero-, or multi metallic complexes and clusters, catalytically active coordination complexes and other defined nanostructures forming ternary complexes with any small molecule with appreciable vapor pressure beyond water.



ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. The individual VT-MS spectra, details on the synthesis and characterization of coordination complexes is provided.

AUTHOR INFORMATION Corresponding Author * E. Boros, C. J. Johnson, Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, NY 11790 E-mail:[email protected], [email protected] †

These authors have contributed equally.

ACKNOWLEDGMENT E.B. acknowledges funding sources, specifically the NIH for a Pathway to Independence Award (NHLBI R00HL125728-04), a REACH award (U01HL127522 – 18150031) and Stony Brook University for startup funds. C.J.J. acknowledges support from the U.S. National Science Foundation (CHE-1566019) and American Chemical Society Petroleum Research Foundation (PRF 58133DNI6). We thank Anthony Cirri and Hanna Morales Hernandez for assistance with data acquisition, and Shin-Hye Ahn for preparing the DFO complexes. Peter Caravan is thanked for helpful discussions during the preparation of this manuscript.

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VT-MS spectrum

q=1

VT-MS speciation 1.0

M

Relative Abundance

1 2 3 4 5 6 7 8 9 10 11 12 13 14

q=0

M 0

10 20 Δ m/z

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q =q0= 0 200 240 280 Temperature (K)

A General Approach to Direct Measurement of the ... - ACS Publications

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