Holmium-DOTA complex Polyhedron

Polyhedron 79 (2014) 277–283

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Paramagnetic lanthanides as magnetic resonance thermo-sensors and probes of molecular dynamics: Holmium-DOTA complex Sergey P. Babailov a,⇑, Peter V. Dubovskii b,c, Eugeny N. Zapolotsky a a

A.V. Nikolaev Institute of Inorganic Chemistry, The Siberian Branch of the Russian Academy of Sciences, Av. Lavrentyev 3, Novosibirsk 630090, Russian Federation Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10 Miklukho-Maklaya str., Moscow 117997, Russian Federation c A.V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 29 Leninsky av., Moscow 119991, Russian Federation b

a r t i c l e

i n f o

Article history: Received 17 February 2014 Accepted 29 April 2014 Available online 15 May 2014 Keywords: Lanthanide complexes Conformational molecular dynamics Dynamic NMR DOTA Magnetic resonance thermo-sensor

a b s t r a c t Investigation of lanthanide (Ln) chelates and their paramagnetic properties with NMR spectroscopy is an established area of research. However, respective data for coordination compounds of holmium (Ho) are scarce. To fill this gap, the present work focuses on detailed determination of intramolecular dynamics and paramagnetic properties for holmium complexes. 1H NMR measurements are reported for D2O solutions of paramagnetic [Ho(H2O)(DOTA)] (I) complex in the 273–348 K temperature range. Diamagnetic complex [Lu(H2O)(DOTA)] (II) was used as a reference compound. The spectra obtained have been analyzed using band-shape analysis technique in the framework of dynamic NMR (D NMR). Temperature dependences of lanthanide-induced shifts (LIS) were taken into consideration, too. Conformational dynamic process has been found. The dynamics is caused by an interconversion of square-anti-prismatic (SAP) and twisted-square-anti-prismatic (TSAP) conformers (the estimated activation free energy DGà(298 K) is 65 ± 3 kJ mol1). Thermodynamics of equilibrium between SAP and TSAP conformers of I was investigated too. The results obtained are found to be consistent with those collected for other LnDOTA complexes. In accordance with literature reviewed, the fulfilled experimental study is the first example of intramolecular dynamics determination for holmium complexes. Taking Ho3+ as an example, the methodology of paramagnetic 4f-element probe applications for the study of free-energy changes in chemical exchange processes is discussed. The advantages of this method, compared to D NMR studies of diamagnetic substances are illustrated. Among them is an extension of the range of NMR-accessible rate constants for paramagnetic 4f-element complexes, compared to diamagnetic ones. And last, usage of coordination compounds investigated as a new type of thermometric NMR sensors and lanthanide paramagnetic probes for in situ temperature control in solutions is demonstrated. The investigated coordination compounds are suggested to apply as thermo-sensing contrast reagent for MRI diagnostics of cancer and inflammation. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction There is growing interest in studies of complexes of lanthanide (Ln) cations, containing O- and/or N-attached ligands (see Refs. [1] {chapter 3.2} and [2–9]). Among them, a special attention is paid to aminopolycarboxylates [10–18]. This is due to broad implementaAbbreviations: CS, chemical shifts; D NMR, dynamic NMR; DNP, dynamic nuclear polarization; H4DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DTPA, diethylenetriaminepentaacetic acid; EDTA, ethylenediaminetetraacetic acid; EXSY, exchange spectroscopy; LISs, lanthanide-induced chemical shifts; Ln, lanthanide; MRI, magnetic resonance imaging; RCA, relaxation contrast reagents; SAP, square-anti-prismatic; TSAP, twisted-SAP. ⇑ Corresponding author. Tel.: +7 (383) 3308957; fax: +7 (3832) 3309489. E-mail address: [email protected] (S.P. Babailov). http://dx.doi.org/10.1016/j.poly.2014.04.067 0277-5387/Ó 2014 Elsevier Ltd. All rights reserved.

tion of their Gd3+ complexes as magnetic resonance imaging (MRI) relaxation contrast reagents (RCA) [5–7,9–10]. For diagnostic purposes, these compounds are injected intravenously to alter the water proton relaxation times in tissues [5–7,9–10]. As a result, image contrast and information content improve significantly. Moreover, these compounds (e.g. Ln-EDTA and Ln-DTPA complexes; Ln = Gd, Dy and Ho) were used for achieving high levels of nuclear spin polarization at experiments on the dynamic nuclear polarization (DNP) enhancement [17,18]. They could also be of value in the context of a simple low-cost method of achieving several-hundred-fold improvements in polarization for experiments in which samples are pre-polarized at low temperatures, then rewarmed and dissolved immediately prior to analysis.

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In particular, the lanthanide complex [Gd(DOTA)] (H4DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is considered as the perfect lead compound of RCA for MRI and prospective reagent for DNP. This is due to its very high thermodynamic and kinetic stability, combined with the favorably long electronic relaxation time [1,2,9]. Moreover, because of high stability of Ln complexes with DOTA and DOTA-like (see detailed description of the term and related molecular structures in [3,12]) ligands, they are broadly utilized in science and practice as metal chelating low-molecular weight adducts for protein and other biomolecule conjugates, nanoparticles, biological and medical sensors. LnDOTA-like complexes may also be considered as models for the actinide complexes formed at chelation therapy (in case of internal human actinide contamination) [3,7,12]. Therefore, there is definite interest in studies of the relationship between structure, paramagnetic properties and molecular dynamics in Ln-DOTA complexes. This information brings about detailed understanding of the processes occurring in the solvated Ln complexes with DOTA and DOTA-like ligands [10–16]. It should be noted that structure, thermodynamics, inter- and intra-molecular dynamics of many complexes between Ln3+ and aminopolycarboxylate have been studied in very detail [10–20]. Of mention, 1H NMR relaxation spectroscopy was used to investigate intermolecular dynamics in [Gd(H2O)(DOTA)] complexes, caused by an exchange of water molecules between bound and free states [19,20]. Previously, intramolecular conformational dynamics in DOTA and DOTA-like complexes of La3+, Eu3+ and Yb3+ was studied by a combined approach, based on 2D EXSY and NMR-determination of the coalescence temperatures [11]. For other Ln3+ cations the dynamic properties of [Ln(H2O)(DOTA)] complexes are unknown. Efforts to study Ho-DOTA complexes were continuously undertaken earlier [12]. Nevertheless, conformational dynamics of these complexes have not been studied comprehensively. Furthermore, from the literature reviewed we did not find a paper where the holmium complex intramolecular dynamics was presented. The goal of the present work is a detailed study of the intramolecular conformational dynamics in [Ho(H2O)(DOTA)] complexes (I) with the use of 1H NMR line-shape analysis. Taking into account data on temperature dependence of lanthanide-induced shifts (LIS), conformational intramolecular dynamics of complexes I is assayed. We also investigated thermodynamics of the conformer equilibrium for the system I. Diamagnetic complex [Lu(H2O) (DOTA)] (II) was used as a reference compound [1,2,9]. Taking Ho3+ as an example, the methodology of paramagnetic 4f-element probe applications for the study of the free-energy variation in chemical exchange processes is discussed. Advantages of this method, compared to D NMR studies of diamagnetic substances, are revealed. In particular, extension of the range of the NMR determined rate constants for paramagnetic 4f-element complexes, compared to diamagnetic ones, is demonstrated. And last, for practical applications, the usage of investigated coordination compounds as new type thermometric NMR sensors and Ln paramagnetic probes for in situ temperature control in solution and can be recommended. The [Ho(H2O)(DOTA)] complex is considered to be thermo-sensing contrast reagent for MRI diagnostics of cancer and inflammation and potential new functional material.

atoms. A pair of conformational isomers, square-anti-prismatic (SAP) and twisted-square-anti-prismatic (TSAP) (Scheme 1) exists for the complexes in solution and crystal. They differ in the mutual orientation of the parallel planes formed by the Ln-bound N- and O-atoms (see Scheme 1). The twist angles between these planes are about +40 and 24° corresponding to square antiprismatic (SAP, often labeled M) and twisted square antiprismatic (TSAP, often labeled m) coordination geometries, respectively (see also Section 2 and Scheme 1 in Ref. [16]). For the [Ln(H2O)(DOTA)] complexes relative amounts of the conformers in solution depends on Ln cation type [13]. For solutions of the heavy Ln complexes, to which Ho belong, SAP form prevails over TSAP one [11,13,14]. To assign the signals in the 1H NMR spectra, theoretical LIS for Ho-DOTA complexes were calculated within the framework of the following model. The calculations were based on the LIS data, available for Yb-DOTA complex [11]. A similar spatial organization of Ho and Yb complexes was assumed. Fermi-contact contributions to LIS were considered small, compared to pseudocontact one, and were neglected. In general, theoretical spectra for [Ho(H2O)(DOTA)] and experimental chemical shifts are fairly agreed (Table 1). Besides that, we compared assignments obtained with those available for the complex of Ho with DOTA-like ligand [12]. We found full correspondence between the spectra and assignments made in the both cases. Thus, the analysis of the CS, made according to Bleaney’s method [9,21,22], and comparison to the spectra of the parent compound, allowed us to obtain satisfactory assignments of the experimental LIS in the Ho-DOTA complex. Scheme 1 depicts an interconversion between SAP and TSAP conformers in the [Ln(H2O)(DOTA)] complex. We investigated the band-shapes of the zero-order 1H NMR spectra of the [Ho(H2O)(DOTA)] complex over a temperature range from 273 to 348 K. Thus, the activation free energy for the intramolecular dynamics in I was evaluated (see Section 2.2). Also, a comparison was made between thermodynamic parameters of the intramolecular dynamic processes within

2. Results and discussion 2.1. Qualitative interpretation and signal assignment DOTA is known to be an 8-dentate ligand, forming 8-coordinated complex with Ln cations. As many as 4 metal–ligand bonds are formed by the nitrogen atoms of the macrocycle. The remaining 4 bonds are formed via coordination of iminoacetate oxygen

Scheme 1. Molecular dynamics in Ln-DOTA system.

279


Table 1 Experimental (Ddex, ppm) and calculated (Ddcalc, ppm) 1H NMR lanthanide-induced shifts in Ln-DOTA complexes; hydrogen atoms of the DOTA ligand designation in SAP*** and TSAP* conformers. Designation of H atoms** in [Yb(DOTA)]

Ddex** in [Yb(DOTA)] (T = 298K)

Ddcalc in [Ho(DOTA)] (T = 300 K)

Ddex for a mixture of [Ho(H2O)(DOTA)] and [Ho(DOTA)] (T = 300 K)

Designation of H atoms in [Ho(H2O)(DOTA)]

SAP ax1 ax2 e1 e2 ac1 ac2

133 47 24 20 38 82

236 83 43 35 67 145

242,64 86,85 55,41 – 53,55 160,99

SAP ax1 ax2 e1 e2 ac1 ac2

TSAP ax1* ax2* e1* e2* ac1* ac2*

80 32 15 10 25 54

142 57 27 18 44 96

124 53,54 35,62 34,7 39,33 104,49

TSAP ax1* ax2* e1* e2* ac1* ac2*

*

See Scheme 2. See Ref. [11]. *** See Scheme 3. **

a series of relational metal complexes. An extra-sensitivity was gained via use of a high-field NMR spectrometer (Avance 800, see Material and Methods for details) equipped with a cryoprobe. In Fig. 1 the temperature dependence of 1H NMR spectra of the complex I is presented. There are four signals in the spectrum obtained at low temperature of 273.2 K. They correspond to the protons of the acetate groups of TSAP (see Scheme 2) and at least two broadened signals of SAP protons (Scheme 3). The signals at 190, 102, 63, and 63 ppm correspond to the SAP conformer. Moreover, the signals with attenuated intensities (at 42 and 39 ppm) are seen due to extra-sensitivity gained. Probably, they correspond to the minor TSAP conformer of the complex I. The halfwidth of the signals of the SAP conformer decreases with temperature increase in the 273–310 K temperature range. A similar observation can be made for the halfwidths of the signals, corresponding to the TSAP conformer. It seems, these changes can

be partially explained by fast intermolecular dynamics, caused by an exchange of water molecules between the complex associated and the free states (see Scheme 4). This type of intermolecular dynamics was previously investigated by 17O NMR [14,40]. According to information from Refs. [14,40], the mechanism of H2O exchange in [Ln(H2O)(DOTA)] complexes appeared to be dissociative. This chemical exchange (Scheme 4) is accompanied with variation in the coordination polyhedron of Ho cation. As a result, the parameters of the anisotropy of paramagnetic susceptibility undergo a change and the chemical shifts of the same protons in the [Ln(DOTA)] and [Ln(H2O)(DOTA)] complexes exhibit substantial variation. On the other hand, these changes can be rationalized by the Curie contribution to 1/T2. It is directly proportional to the square of the applied magnetic field. It is clear therefore that this contribution will be important at 18.8 T

Fig. 1. Variable temperature dependence of 800 MHz 1H NMR spectra of [Ho3+(H2O)(DOTA4)], in D2O; chemical shift values (d scale) are relative to internal 4,4-dimethyl 4silapentane sodium sulfonate (DSS); at temperatures (T, K): 273 (1), 288 (2), 300 (3), 310 (4), 318 (5); signal at 4.8 ppm. corresponds to HDO.

280


[Ln( DOTA)]- + H 2O

→ ←

[ Ln( H 2O)( DOTA)]-

Scheme 4. Proposed intermolecular dynamics in Ln-DOTA system.

Scheme 2. Designation of hydrogen atoms in TSAP conformer.

(800 MHz), as it has been already shown to be significant at considerably lower magnetic fields [1,23]. This can be clearly observed by a comparison of the 1H NMR spectra shown in Figs. 1 (800 MHz) and 2 (300 MHz). The resonances in Fig. 1 are clearly broader than those observed at 300 MHz. Apart from the dependence of the Curie contribution with the magnetic field, it also depends on 1/T2, and therefore increasing the temperature is expected to decrease this contribution and therefore the linewidths. Thus, the effect of temperature on the linewidths observed in Fig. 1 can be attributed to the Curie contribution and can be related (in part) with intermolecular dynamic process. It should be noted that we could not record signals ac2, ax1 and ax2, even with special cryoprobe. Firstly, it is because of the concentration of TSAP molecular form is less than the concentration of SAP conformer. Second, signals ac2, ax1 and ax2 are broadened due to valuable the paramagnetic lanthanide-induced enhancement of relaxation rates [1,2,9]. 2.2. Intramolecular dynamics The signals of SAP and TSAP conformers, being rather narrow at low temperatures, begins to broaden, when temperature increases in the range from 310 to 348 K (line broadening progresses with

temperature increase; see Fig. 2). As can be seen from Fig. 2, the signals of SAP protons disappear completely at the temperatures above 314 K (the spectra were acquired at a 300 MHz-spectrometer). Of note, temperature increase results in a change of the lineshape of NMR signal, corresponding to hydrogen atoms of CH2 groups in the complexes I. The lineshape is characteristic for CE system (Fig. 2). The observed lineshape variations are quite typical for the systems, where a low-populated component (in this case, this is TSAP conformer) exchanges with a high-populated one (SAP conformer). This lineshape variation is likely due to conformation dynamics, caused by interconversion between SAP and TSAP conformers. Conformational dynamics of this type, presented in Scheme 1 takes place in aqueous solutions of Ho-DOTA complexes. A quantitative analysis of the lineshape variation of these signals enabled us to estimate the rate constants of the CE process at different temperatures and to determine the activation free energy (Table 2, Fig. 3). The ionic radii for these cations are also presented in Table 2. The data obtained are presented in Fig. 3. From these data we calculated the activation free energy (see Experimental section, Eq. (2)) DGà(298 K) = 65 ± 3 kJ mol1. As we can see from Table 2, the value of the activation free energy is comparable to the energy barrier height for conformational transitions in DOTA-like complexes, encompassing a variety of metal cations, obtained by different teams [11–14]. The rate constants for this dynamic process fall in the range of 18–180 s1. The activation free energy of exchange between these conformers falls in the 60– 65 kJ mol1 range for most of Ln-DOTA complexes (Table 2). One can see from Table 2 that the magnitude of the activation free energy for these DOTA complexes increases in the order from La to Yb. According to our viewpoint, this monotonic increase of the free energy of the intramolecular exchange in the series of lanthanide [Ln(DOTA)] complexes is related to decrease of the ionic radii in lanthanides, known as the ‘‘lanthanide contraction’’ [9,28]. The concentration of I appeared to have no influence on the rate constant of molecular dynamics (studied between 103 and 102 mol/dm3), i.e., interconversion of the isomers is obviously a first-order reaction. Discussing the obtained values of the activation free energy for DOTA molecular dynamics in the complexes under investigation, we have to note the following. The discovered magnitude of the activation free energy is commensurable with the values of the energetic barriers of conformational inversion in 18-crown-6 molecules of [Ln(18-crown-6)(NO3)3] complexes (where DGà(310 K) appeared to be 58 ± 6, 49 ± 6, and 45 ± 5 kJ mol1 for Pr, Ce and Nd, respectively [25]). However, in the [Ln(18-crown-6)(NO3)3] complexes observed decrease in the free energy of a number of metals, rather than increasing as in [Ln(DOTA)] complexes. The intramolecular dynamics in the macrocyclic molecule investigation results may be relevant for understanding some of their other physicochemical properties, for example, reactivity, reaction mechanism, etc. 2.3. Thermodynamics of the Isomer equilibrium

Scheme 3. Designation of hydrogen atoms in SAP conformer.

Although an estimate of the ratio between isomers for [Ln(DOTA)] complexes (where Ln = Er, Tm, Yb and Lu) has already been reported [13], we obtained it here for holmium complex at different temperature. Table 3 reports thermodynamic parameters (equilibrium constant, reaction enthalpy and entropy) describing reaction of an equilibrium exchange between SAP and TSAP

281


Fig. 2. Variable temperature dependence of 300 MHz 1H NMR spectra of [Ho(H2O)(DOTA)], in D2O; chemical shift values are relative to DSS (d scale); at temperatures (T, K): 314 (1), 319 (2), 328 (3), 338 (4), 348 (5).

isomers for [Ho(H2O)(DOTA)] complex. The values found are also comparable to the values for other Ln, reported elsewhere [13]. The magnitude of the reaction enthalpy (describing reaction of an equilibrium exchange between SAP and TSAP) decreases in the order from Ho to Lu (Table 3). A decrease of DH° in the series of lanthanide [Ln(DOTA)] complexes may be also related to the ‘‘lanthanide contraction’’.

2.4. Paramagnetic probes based on 4f elements for D NMR at high magnetic fields There is a peculiarity of D NMR use for studies of paramagnetic compounds of 4f elements, deserving of a special comment to be made on. The range of measurable paramagnetic LISs is known to exceed above 100 ppm. Due to paramagnetic chemical shifts (dm) in 4f complexes, the range of measurable rate constants expands considerably, compared to the respective range in diamagnetic compounds. This may be illustrated for a system with a degenerate two-site exchange process. For NMR spectrometer, whose operating frequency for protons is 800 MHz, the highest value of the rate constant, accessible to measurements is kmax 1010 Hz (upper limit). Thus, it can be assumed that dm = 8 104 Hz, or 100 ppm in paramagnetic compounds. Let us assume that an error in halfwidth determination is about 1 Hz. The kmax value in paramagnetic compounds is much larger than the kmax (108 Hz) in diamagnetic compounds (dm 8 103 Hz). The lower limit for the range of the rate constant becomes kmin 1 Hz. Thus, using the paramagnetic probe method for

investigation of the intramolecular dynamics of ligands, coordinated to this metal cation, is equivalent to using of an NMR spectrometer with an unprecedented high operating frequency of 8 GHz. Therefore, the potential of this method in studies of molecular dynamics of various ligand complexes with paramagnetic metal cations is significantly higher than in the case of complexes with diamagnetic cations. In the present paper, using variable-temperature 1H NMR, conformational dynamics of Ho3+ complex in the 319–348 K temperature range was investigated (Fig. 2). The maximum rate constant of the conformational dynamics was estimated to be 3.4 103 s1 at 348 K. 2.5. Temperature dependence of paramagnetic LIS and thermo-sensing The temperature dependencies of paramagnetic LISs of [Ho(H2O) (DOTA)] for protons of different groups are presented in Fig. 4. As seen in Fig. 4, experimental paramagnetic LIS values (dobs ddia) are well fitted by linear dependence on 1/T (Curie–Weiss approximation) [9,24–28]:

dobs ddia ¼ a þ b=T

ð1Þ

It is known that Fermi contact contribution to LIS is proportional to 1/T (Curie’s law). From theoretical standpoint [21], the pseudocontact contributions to LIS is proportional to 1/T2 (it was calculated in the second approximation). Concerning experimental investigations, some of them confirmed the 1/T2 dependence. Nevertheless, in many cases, there was no control of the

Table 2 Activation free energies (DGà298, kJ mol1), derivative of experimental lanthanide-induced shifts (d(Ddex)/dT, ppm/K) and methods used for investigation the intramolecular dynamics in DOTA-like lanthanide complexes.

#

Complex

Radius/ Å**

Activation free energy/(kJ mol1), DGà298

Rate constants of CE k298, s1

Method

d(Ddex)/dT, ppm/ K

Ref.

[La(DOTA)]

1.16

60.7 ± 1.2

–

1

0.0

Desreux et al. [11]

[Nd(DOTA)] [Eu(DOTA)] [Eu(DOTAM)] [Eu(DOTA-like)] [Ho(OH2)(DOTA)] Na[Tm(DOTP)]

1.11 1.07 1.07 1.07 1.02 0.99

– 63 54.6 – 65 ± 3 –

– – k250 = 68 ± 5 k293 = 45 ± 15 k319 = 180 ± 20 –

0.1& – – 0.19& 1.0 1.17&

[Yb(DOTA)] [Lu(DOTA)]

0.99 0.98

65.6 65.9 ± 1.2

k298 = 33 ± 3 k298 = 18

Aime et al. [10] Aime et al. [13] Dunand et al. [14] Woods et al. [40] This paper Trubel et al. 2003 [39] Desreux et al. [11] Aime et al. [12]

H and 13C BSA# 13 C 1 H BSA# 1 H BSA# 1 H 2D EXSY 1 H BSATD–LIS* 1 H 1

H 2D EXSY H and 13C BSA#

1

0.22& 0.0

BSA means band shape analysis technique within the framework of the dynamic NMR. BSATD-LIS means band shape analysis taking into account temperature dependence of LIS within the framework of the dynamic NMR. & Our calculations. ** Data for complexes with coordination number 8 (see Ref. [41]). *

282


Fig. 3. Dependence of ln(k/T) on 1/T, where k is the rate constant of the intramolecular dynamic process in [Ho(H2O)(DOTA)], T is the temperature, and D2O as the solvent.

thermodynamic and kinetic stability of complexes. In some cases this was confirmed. We support the viewpoint that the temperature relationship of LIS depends heavily on higher-order states, but for practical purposes, the experimental dependence in the 200–350 K temperature range is described by the Curie–Weiss approximation adequately [9,24–28]. This result correlates well with studies of [Ln(H2O)(EDTA)] (Ln = Pr, Er, Ho, Tm and Yb) complexes [26–31,36], [Ln (18crown-6) (ptfa)2]+ [9,30–33], [Ln(diaza-18-crown-6)(NO3)3] [9], [Ln(18-crown-6)(NO3)3] (where Ln = Ce, Pr and Nd) [9,23–25,28], and [LnH(oep)(tpp)] (where Ln = Dy and Yb, ptfa is 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedione, tpp is tetraphenylporphyrin, and oep is octaethylporphyrin) [38]. One can use this linear temperature relationship of LIS in practice. Recently, we proposed to use this temperature dependence of paramagnetic LISs for in situ temperature control in both aqueous [26–29,36,37] and nonaqueous media [24–28,32–35]. We also investigated experimental paramagnetic LISs Ddex(T) versus T. The derivative of Ddex(T) was calculated (see Table 2). The signal of the ax1 H atom (242,6 ppm at 300 K) exhibit maximum temperature gradient, amounting to 1.0 ppm/K. The value found is much larger than that for the temperature gradient of pure water (0.01 ppm/K). This temperature sensitivity corresponds to uncertainty in the estimation of the temperature of 0.03 K (assuming the error of the chemical shift determination to be of 0.03 ppm). It should be noted that maximum d(Ddex)/dT value in I is larger than those for many other lanthanide chelates and comparable to that for Na[Tm(DOTP)]2 (see Table 2). Of note, our previous NMR investigations of lanthanide complexes were carried out mainly in organic solvents [9,26–34]. In this paper the results are presented for aqueous solutions. The temperature dependencies of LISs revealed for Ln complexes in aqueous solutions, might have practical importance for biological and medical applications. In particular, [Ho(H2O)(DOTA)] complex might be used as a subnanoscale NMR spectroscopic probe for local temperature determination in aqueous media. It can be

Table 3 Reaction enthalpies and entropies for the isomer equilibrium reaction SAP = TSAP of [Ho(OH2)(DOTA)] complexes (KT = [TSAP]/[SAP]). Ln

K298

DH°, kJ mol1

DS°, J mol1 K1

Ref.

Ho Er Tm Yb Lu

0.04 ± 0.01 0.03 0.08 0.20 0.18

20 ± 1.1 – 16.2 ± 0.9 17.5 ± 0.7 10.1 ± 0.1

39 ± 5 – 33 ± 3 45 ± 2 18 ± 1

This paper [13] [13] [13] [13]

[TSAP] and [SAP] are concentration of TSAP and SAP, respectively.

Fig. 4. Temperature dependence of the paramagnetic LISs in 800 MHz 1H NMR spectra for ac2 (), ax2 (j), ac1 (N) protons of the SAP conformer of [Ho(H2O) (DOTA)] dynamic system, with D2O as the solvent.

done (for example for the ac2 signal) as follows. After determining the value of the paramagnetic contribution to chemical shift at some point, one can find the local temperature using the ac2 dependence of LIS shown in Fig. 4. Favorably, this complex can be used as thermometric NMR sensors either in reaction media directly, or in situ studies of exothermic or endothermic processes. Also, I can be applied for control of local temperature in medical magnetic resonance imaging for in vivo three-dimensional mapping of the body-temperature distribution and diagnostics of different body parts in diseases, including those related to cancer. 3. Experimental section The [Ho(H2O)(DOTA)] complexes were prepared, according to ref [12]. Solutions in D2O had the concentration of complexes C = 10–2 M (at pD = 7.0). The pD values were measured in a galvanic cell by a microprocessor-equipped pH-meter/ionmer Anion-410 of Infraspak-Analyt (Novosibirsk) and pocket-sized pH-meter with replaceable electrode of HANNA Instruments. The glass electrode, combined with a silver/silver chloride reference electrode, filled with a saturated potassium chloride solution, was used. The cell volume was of 2 ml. The pD measurement precision was 0.05. The combined electrode was calibrated, using a set of reference solutions in D2O: (1) 0.05 M potassium citrate, (2) 0.025 M KH2PO4 and 0.025 M Na2HPO4 mixture of phosphates, and also (3) 0.025 vNaHCO3 and 0.025 M Na2CO3 mixture of carbonates. The volume of solutions was 10–20 ml. For these solutions the pD values (25 °C) of 4.29; 7.43, and 10.74, respectively, were assumed [28,29]. The 1H NMR spectra were measured with MSL-300 and Avance800 spectrometers (all produced by Bruker, Germany). The operating frequency was 300.31 and 800.13 MHz, respectively. The highfield spectrometer was equipped with a cryoprobe. The residual proton signal in D2O (4.75 ppm at 303 K) was used for chemical shift referencing. Through all the measurements the magnetic field was stabilized, using deuterium lock of the solvent. The spectra were measured in the tubes with an outer diameter of 5 mm. A B-VT-1000 temperature unit with the accuracy of 1 K and stability of 0.2 Kh1 was used for temperature control. The unit was


calibrated, using standard samples with known temperature dependence of chemical shifts. Studies of exchange-broadened NMR spectra were carried out by line-shape analysis within the framework of D NMR [9,24–28]. Paramagnetic LISs were determined relative to diamagnetic complex II, which served as a reference (as in Refs. [9,10]). As it can be seen in Fig. 4, experimental LIS values are well fitted, assuming their linear dependence on 1/T. As required for NMR line-shape analysis, LIS values of protons signals in the absence of either intermediate, or fast exchange on the NMR time-scale [9,24–28], were calculated, according to the following equation:

Ddi ðTÞ ¼ Ddi ðT 0 Þð1=T þ AÞ=ð1=T 0 þ AÞ

ð2Þ

Parameter A was defined by analysis of average LIS value for ac2 proton, T0 = 273 K. Eq. (2) serves to determine the chemical shift (for different signals) depending on the temperature. The free energy of activation, DGà, of molecular dynamics in [Ho(H2O)(DOTA)] was calculated according to the Eyring equation [9,24–27],

k ¼ ðKkB T=hÞexpðDGz =RTÞ

ð3Þ

where k is the rate constant of chemical exchange reaction, T is the absolute temperature, R is the gas constant, kB is Boltzmann’s constant, h is Planck’s constant and K is the coefficient, dependent on unit measures. 4. 1H NMR spectral assignments [Ho(H2O)(DOTA)] (SAP ). dH (ppm, 190.57 (N–CH2–COO, ac2, s); 102.26 63.62 (N–CH2–COO, ac1, s); 64.35 280.48 (N–CH2–COO, ax1, s). [Ho(H2O)(DOTA)] (TSAP). dH (ppm, 41.98 (N–CH2–COO, ac1, s); 40.17 40.64 (N–CH2–CH2–N, e2, s).

D2O, pD = 7, T = 273.2 K): (N–CH2–CH2–N, ax2, s); (N–CH2–CH2–N, e1, s); D2O, pD = 7, T = 273.2 K): (N–CH2–CH2–N, e1, s);

5. Conclusion The present work is the first-ever study, reporting the parameters of intramolecular dynamics of paramagnetic holmium complex with DOTA4 in aqueous media, elucidated by 1H NMRspectroscopy. With holmium complexes as an example, this method proves to be effective for studies of molecular dynamics in paramagnetic lanthanide chelates. Conformational dynamic process was investigated (it is caused by an interconversion of SAP and TSAP conformers of the complex). The activation free energy was estimated to be DGà(298 K) = 65 ± 3 kJ mol1. The fulfilled experimental study is the first example of intramolecular dynamics determination for holmium complexes. The results obtained are consistent with those collected for other Ln-DOTA complexes. For practical purposes, the complexes of DOTA4 with Ho3+ might be used as a nanoscale NMR spectroscopic probes to determine temperature in aqueous media and thermo-sensing contrast reagent for MRI diagnostics of cancer and inflammation.

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Acknowledgment The authors are grateful to Professors V.P. Fedin and A.S. Arseniev for useful discussions. The work was fulfilled with the partial financial support of the Russian Foundation for Basic Research (Grant N14-03-00386-a). We thank A.S. Babailova for a technical assistance in the design of drawings. References [1] C. Piguet, C.F. Geraldes, Handbook on the Physics and Chemistry of Rare Earths, Elsevier Science, Amsterdam, 2003. [2] D. Parker, R.S. Dickins, H. Puschmann, C. Crossland, J.A.K. Howard, Chem. Rev. 2002 (1977) 102. [3] J. Koehler, J. Meiler, Prog. Nucl. Magn. Reson. Spectrosc. (2011), http:// dx.doi.org/10.116/g.pnmrs.2011.05.001. [4] G. Otting, Annu. Rev. Biophys. 39 (2010) 387. [5] K. Riehemann, S.W. Schneider, T.A. Luger, B. Godin, M. Ferrari, H. Fuchs, Angew. Chem., Int. Ed. 48 (2009) 872. [6] B. Godin, J.H. Sakamoto, R.E. Serda, A. Grattoni, A. Boumarini, M. Ferrari, Trends Pharmacol. Sci. 31 (5) (2010) 199. [7] A.E.V. Gorden, J. Xu, K.N. Raymond, Chem. Rev. 103 (2003) 4207. [8] V.K. Voronov, Russ. Chem. Rev. 79 (2010) 835. [9] S.P. Babailov, Prog. Nucl. Magn. Reson. Spectrosc. 1 (2008) 1. [10] S. Aime, M. Botta, G. Ermondi, Inorg. Chem. 31 (1992) 4291. [11] V. Jaques, J.F. Desreux, Inorg. Chem. 33 (1994) 4048. [12] S. Aime, M. Botta, G. Ermondi, E. Terreno, P.L. Anelli, Inorg. Chem. 35 (1996) 2726. [13] S. Aime, M. Botta, M. Fasano, M.P.M. Marques, C.F.G.C. Geraldes, D. Pubanz, A.E. Merbach, Inorg. Chem. 36 (1997) 2059. [14] F.A. Dunand, S. Aime, A.E. Merbach, J. Am. Chem. Soc. 122 (2000) 1506. [15] S. Zhang, K. Wu, A.D. Sherry, J. Am. Chem. Soc. 124 (2002) 4226. [16] F. Mayer, C. Platas-Iglesias, L. Helm, J.A. Peters, K. Djanashvili, Inorg. Chem. 51 (2012) 170. [17] J.W. Gordon, S.B. Fain, I.J. Rowland, Magn. Reson. Med. 68 (2012) 1949. [18] D.T. Peat, A.J. Horsewill, W. Koeckenberger, A.J.P. Linde, D.G. Gadian, J.R. Owers-Bradley, Phys. Chem. Chem. Phys. 20 (2013) 7586. [19] K. Micskei, L. Helm, E. Brucher, A.E. Merbach, Inorg. Chem. 32 (1993) 3844. [20] S. Aime, A. Barge, J.I. Bruce, M. Botta, J.A.K. Howard, J.M. Moloney, D. Parker, A.S. Sousa, M. Woods, J. Am. Chem. Soc. 121 (1999) 5762. [21] B. Bleaney, J. Magn. Reson. 25 (1972) 91. [22] J. Maigut, R. Meier, A. van Zahl, R. Eldik, Inorg. Chem. 47 (2008) 5702. [23] S.P. Babailov, E.N. Zapolotsky, E.S. Fomin, Polyhedron 65 (2013) 332. [24] J. Sandstrom, Dynamic NMR Spectroscopy, Academic Press, London, 1975. [25] S.P. Babailov, Inorg. Chem. 51 (3) (2012) 1427. [26] S.P. Babailov, P.A. Stabnikov, E.N. Zapolotsky, V.V. Kokovkin, Inorg. Chem. 52 (9) (2013) 5564. [27] S.P. Babailov, Paramagnetic NMR: Molecular Structure and Chemical Exchange Processes in d- and f-Element Coordination Compounds in Solution, LAP Lambert Academic Publishing, Saarbrücken, 2012. p. 84. [28] S.P. Babailov, J.H. Krieger, Russ. J. Struct. Chem. 39 (4) (1998) 714. [29] M. Paabo, R.G. Bates, Anal. Chem. 41 (2) (1969) 283. [30] R.G. Bates, Determination of pH, Theory and Practice; John Wiley, New York, 1973. [31] S.P. Babailov, Russ. Chem. Bull. 6 (2008) 1292. [32] S.P. Babailov, P.A. Stabnikov, V.V. Kokovkin, Russ. J. Struct. Chem. 51 (2010) 682. [33] S.P. Babailov, J.H. Krieger, T.N. Martynova, L.D. Nikulina, J. Struct. Chem. (USSR) 31 (1990) 44. [34] S.P. Babailov, L.D. Nikulina, J.H. Krieger, J. Incl. Phenom. 43 (2002) 25. [35] S.P. Babailov, D.A. Mainichev, J. Incl. Phenom. 43 (2002) 187. [36] S.P. Babailov, J.H. Krieger, Russ. J. Struct. Chem. 39 (1998) 714. [37] S.P. Babailov, Magn. Reson. Chem. 50 (2012) 793. [38] S.P. Babailov, A.G. Coutsolelos, A. Dikiy, G.A. Spyroulias, Eur. J. Inorg. Chem. 1 (2001) 303. [39] H.K.F. Trubel, P.K. Maciejewski, J.H. Farber, F. Hyder, J. Appl. Physiol. 94 (2003) 1641. [40] M. Woods, S. Aime, M. Botta, J.A.K. Howard, J.M. Moloney, M. Navet, D. Parker, M. Port, O. Rousseaux, J. Am. Chem. Soc. 122 (2000) 9781. [41] P.Di. Bernardo, A. Melchior, M. Tolazzi, P.L. Zanonato, Coord. Chem. Rev. 256 (2012) 328.