Air-Stable Gadolinium Precursors for the Facile Microwave-Assisted

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Air-Stable Gadolinium Precursors for The Facile Microwave-Assisted Synthesis of GdO Nano-contrast Agents for Magnetic Resonance Imaging 2

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Johannes Schlaefer, Shaista Ilyas, zhangjun Hu, Kajsa Uvdal, Martin Valldor, and Sanjay Mathur Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00787 • Publication Date (Web): 10 Jan 2018 Downloaded from http://pubs.acs.org on January 11, 2018

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Crystal Growth & Design

Air-Stable Gadolinium Precursors for The Facile Microwave-Assisted Synthesis of Gd2O3 Nano-contrast Agents for Magnetic Resonance Imaging †

†

†

‡

‡

§

Shifaa M.Siribbal , Johannes Schläfer , Shaista Ilyas , Zhangjun Hu , Kajsa Uvdal , Martin Valldor , †,* Sanjay Mathur †

Institute of Inorganic Chemistry, University of Cologne, Greinstraße 6, 50939 Cologne Germany.

§

Max Planck Institute for Chemical Physics of Solids, Nöthnitzer Strasse 40, 01187 Dresden, Germany.

‡

Division of Molecular Surface Physics and Nanoscience, Department of Physics, Chemistry, and Biology (IFM), Linköping University, Linköping 58183 Sweden.

Abstract Using metal organic precursors in materials synthesis remains a challenge due to their high moisture susceptibility. In this work, we described a facile methodology for the synthesis of Gd2O3 based contrast agents from two new gadolinium-based complexes. [Gd(PyTFP)4] (PyH) 1 (PyTFP = C8H5NOF3, Py = C5H5N) and [Gd(DMOTFP)3Py] 2 (DMOTFP = C8H7NO2F3) were synthesized via a classical ligand exchange reaction of [Gd{N(SiMe3)2}3] under inert conditions. As a result, X-ray diffraction analysis revealed a distorted square anti-prismatic coordination and an augmented triangular prismatic arrangement of ligands around gadolinium atoms in 1 and 2, respectively. It also showed that 1 is an anionic complex of formula [Gd(PyTFP)4](PyH), while a neutral tris-compound, [Gd(DMOTFP)3Py] was obtained as pyridine adduct in 2. A fast and reproducible microwave-assisted decomposition of 1 and 2 provided homogeneous Gd(OH)3 nanorods at mild temperature without using any surfactant or capping reagent. As-synthesized nanorods were easily transformed into cubic phase of Gd2O3 nanoparticles by thermal treatment under ambient conditions. The magnetic measurement showed the typical paramagnetic behavior of the Gd2O3 NPs. The cytotoxicity profile demonstrates the biocompatibility and negligible toxicity of the as-synthesized nanoprobes. The suggested approach provides a new class of gadolinium based precursors which allows facile synthesis of highly crystalline Gd2O3 NPs. Keywords Gd2O3, precursor, microwave, MRI, contrast agents

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Introduction Due to the high magnetic moment (7.94 µB) caused by the seven unpaired f-electrons, Gd2O3 nanostructures have the capacity to be used as promising materials for T1 contrast agents during magnetic resonance imaging (MRI) process. This unique magnetic moment induces a high longitudinal relaxivity of nearby water protons causing their relaxation.1,2 Particularly, gadolinium-based nanoparticles (NPs) have received mounting attention due to a high density of Gd3+ ions situated on the surface per contrast agent particle.3,4 This results in an increase in the number of water coordination and a higher rotational correlation time in contrast to typical Gd3+ chelates. Since the contrast depends on the actual number of gadolinium ions involved in the relaxivity mechanism of the adjacent water protons, Gd2O3 NPs are considered as a potential candidate in MRI. Moreover, due to their crystalline structure and low solubility; Gd2O3 NPs have a lower toxicity (reduced biosorbance) compared to Gd3+ complexes.5,6 All synthetic approaches for the synthesis of crystalline metal oxide NPs can be categorized into two major classes, colloidal routes or single source precursors method based on the 2


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used precursor.7,8,9,10 In colloid chemistry approach, different metals salts precursors (e.g. chloride, nitrate) are mixed in solution with one or more surfactants at elevated temperature to form crystalline NPs. Although, it is a simple and convenient approach,11,12 but it lacks in the perfect control over size, shape and composition of the as-synthesized materials and need extensive purification steps to remove impurities from the stabilizing agent. On the other hand, single-source precursor’s method involves thermal decomposition of a single molecule (e.g. ß-diketonate, alkoxide) in a hot appropriate coordinating solvent. It generally produces regular NPs at lower temperatures.13,14,15 Nevertheless, such synthesis route demands adequate molecular precursors with a defined chemical composition for the synthesis of desired NPs. In our search towards more intractable and air-stable precursors, we have recently reported on new chelating ligand systems based on substituted heteroarylalkenoles that produce volatile complexes from a number of transition and noble metals as well as felements.16,17,18,19,20 Compared to β-diketonate complexes, the stability of

these

heteroalkenolate complexes is improved due to a pseudo-push-pull effect. Beta-diketonate complexes possess high melting points while alkoxide are sensitive towards air and moisture with respect to their reactivity. Upon complexation, the heteroalkenolate ligands form six-membered metallacycle, which provides both electron-donating inductive effect (+I effect) induced by the heterocycle moiety, and electron withdrawing inductive effect (-I effect) arising from the presence of the –CF3 group. The strong inductive effect of the fluorinated alkyl unit is reflected in the keto-enol tautomerism equilibrium of the free ligands that was investigated by 1H NMR;16 it is affected by the polarity of the solvent and the nature of the fluorine substituent, which is the driving force for shifting the keto-enol equilibrium to enol form. Various method has been developed to synthesize small-sized Gd2O3 NPs based on the use different solvents, stabilizing agents and decomposition approach of gadolinium precursors.21,22, 23 Thermal decomposition methods is not limited for the formation of Gd2O3 particles nevertheless also for synthesizing other gadolinium based nanostructures such as NaGdF4. Generally, replacement reaction between gadolinium chloride and ammonium fluoride in the presence of oleic acid, sodium hydroxide, and 1-octadecene at high temperature were used to prepare NaGdF4 particles. In addition, via hydrothermal methods we do not only synthesize mesoporous Gd2O3 particles but also gadolinium-hydrated 3



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carbonate nanocrystals in the presence of poly (acrylic acid) and pure ethylene glycol.

24,25

More recently a surfactant free chemical approach was applied to prepare biologically compatible Gd2O3 (Eu-doped and undoped) in the presence of gadolinium trisacetylacetone hydrate and benzylalcohol.26 Gadolinium-based molecular precursors have been used in different ways to produce gadolinium oxide nanomaterials. For instance, [Gd(thd)3] (thd = 2,2,6,6-tetramethyl- 3,5-heptanedione) precursor can be used through ALD for the deposition of gadolinium oxide thin film. 27 In addition, volatile gadolinium alkoxide precursor [Gd(mmp)3] complex (mmp=1-methoxy-2-methyl-2-propanolate) has been tested for the deposition of Gd2O3 thin film using liquid injection MOCVD.28 Considering the fact that metal alkoxides are most preferable than beta diketonate in term of growth temperature.29 In our previous work, we have reported the formation of Gd(OH)3 nanorods and nanospheres from solvothermal decomposition of gadolinium oleate and gadolinium tertbutoxide [Gd3(OtBu)9(HOtBu)2], respectively.30 Here, we extended our work using new Gdcompounds in microwave-assisted thermal decomposition reaction. The aim of this study is to provide optimal sized NPs with a shorten synthesis time at mild conditions for contrast enhancement. Based on bidentate chelating ligands 3,3,3-trifluoro-1-(pyridine-2-yl)propen2-ol (PyTFP)17 and 1,1,1-trifluoro-3-[2-(4,5-dimethyloxazolyl)]-propen-2-ol (DMOTFP)16, two air-stable

Gd-based

heteroalkenolates

complexes

were

synthesized.

Namely,

Gd(PyTFP)4(PyH) 1 and (DMOTFP)3(Py) 2 were thermally decomposed in a microwave reaction to obtain homogeneous Gd(OH)3 nanorods, which were further transformed to Gd2O3 upon annealing.

Results & Discussion Synthesis and characterization of the molecular precursors. The substituted β-alkenols 3,3,3-trifluoro-1-(pyridine-2-yl)propen-2-ol HL1 and 3,3,3trifluoro-1-(4,5-dimethylthiazole-2-yl)propen-2-ol HL2 (Figure 1) were synthesized by a trifluoroacetylation of 2-picoline or 2,4,5-trimethyloxazol respectively, in high yields following the procedures previously described by Mathur and coworkers.16,17

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Figure 1: Schematic representation for the used ligands HL1 (left) and HL2 (right).

The replacement of silyl amide ligands [Gd{N(SiMe3)2}3] by alkenole group in toluenepyridine solution occurred instantaneously (Scheme 1). Colorless crystals of the products could be grown out of concentrated toluene solutions and were further subjected to single crystal X-ray diffraction analysis that revealed the coordination of pyridine molecule.

Scheme 1: Synthetic route to asymmetric gadolinium heteroalkenolates Gd(PyTFP)4(PyH) 1 and Gd(DMOTFP)3Py 2.

Both compounds crystallized in the monoclinic space group P 21/c having 4 molecules in the unit cell. Subject to the chemical nature of the ligand the resulting complexes differ significantly in coordination geometry and overall molecular structure. Reaction of gadolinium amide with HL1 produced the anionic complex [Gd(L1)4][PyH] 1, whereas the dimethyloxazol derivative HL2 reacted to the neutral compound [Gd(L2)3(Py)] 2. In complex 1, Gd3+ ion is coordinated by four bidentate ligands building a distorted square antiprismatic coordination sphere. Thereby, each of the opposing basal planes are formed by two trans-standing chelates respectively. A similar coordination motif was already observed for the tetravalent f metal complexes of cerium(IV)

21

and uranium(IV).20 Furthermore, a

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pyridine molecule is located in between two ligands forming one of the square planes (O3N3-O4-N4). The nitrogen is directed towards the alcoholate function (O4) of one of the chelating ligands indicating the formation of a delocalized stabilizing hydrogen bond between N5 and O4. Since all Gd-O and Gd-N bond lengths in the complex are comparable, therefore, It could be assumed that apparently a neutral ligand might coordinated, but since the hydrogen is localized it can also be partially anionic. Nevertheless, the delocalized hydrogen cannot be unambiguously determined by X-ray diffraction and the formation of a neutral complex [Gd(L1)3(L1H)].Py with three deprotonated (L1) and one protonated ligand (L1H) cannot be ruled out.

Figure 2: Molecular structure and coordination polyhedron of 1 (hydrogen atoms are omitted for clarity). Selected bond lengths (Å) and angles (deg.): Gd−O3 2.270(5), Gd−O2 2.280(5), Gd−O1 2.286(4), Gd−O4 2.352(4), Gd−N3 2.600(6), Gd−N1 2.636(6), Gd−N4 2.678(6), Gd−N2 2.680(6), Gd−N5 4.096(6). O1-Gd-N1 71.65(17), O2-Gd-N2 70.49(17), O3-Gd-N3 71.76(18), O4-Gd-N4 68.13(17), O2−Gd−O1 84.78(17), O3−Gd−O2 142.61(17), O2−Gd−N3 80.75(18), O1−Gd−O4 142.20(16).

The Gd center in 2 is coordinated by three alkenolate ligands and one pyridine ligand in an

augmented triangular prismatic geometry (Figure 3). The chelates forming the trigonal prism with the nitrogen base located on the apical position capping the square base. The preference of a seven-fold coordination in place of a square antiprismatic geometry can be explained by the increased steric demand of the ligand L2 induced by the methyl groups of the oxazol substituents. The average Gd-O bond lengths of 2.297 Å (1) and 2.257 Å (2) are 6


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shorter than those typically found for β-diketonates,31,32 but significantly longer than the interatomic distances found for gadolinium alkoxides.33 The mean Gd-N distances vary depending on the ligand due to different basicity of the donor functions (2.649 Å (1), 2.535 Å (L2) and 2.558 Å (Py) (2)) and are consistent with those typically found for gadolinium complexes coordinated by similar nitrogenous bases.34 The larger bond lengths in 1 can be attributed to the ionic nature of the complex and the increased steric repulsion due to the higher coordination number. The bite angles O-Gd-N1 of 71.65 (17), O-Gd-N2 of 70.49 (17), O-Gd-N3 of 71.76(18), O-Gd-N4 of 68.13 (17) in compound 1, and the bite angles O-Gd-N11 of 73.63 (12), O-Gd-N12 of 74.22 (11), and O-Gd-N13 of 72.94 (13) in compound 2 are comparable with those reported in the literature for the same type of bonds.35

Figure 3: Molecular structure and coordination polyhedron of 2 (hydrogen atoms are omitted for clarity). Selected bond lengths (Å) and angles (deg.): Gd–O131 2.253(3), Gd–O121 2.255(3), Gd–O111 2.263(3), Gd–N13 2.512(4), Gd–N11 2.531(4), Gd–N14 2.559(4), Gd–N122 2.560(4). O131–Gd–O121 155.68(12), O131–Gd–N13 72.94(13), O121–Gd–N12 74.22(11), O111–Gd–N11 73.63(12).

Electron Impact Mass Spectrometry (EI-MS). The fragmentation behavior of compounds 1 and 2 was studied using mass spectrometry (EI-MS) (Figure S 1). For compound 1, the peak at m/z = 721 was identified as [Gd(PyTFP)3]+, due to the non-volatile nature of the complex. The fragments at m/z = 534 and m/z = 365 are referred to the cleavage of the second and third ligand to give [Gd(PyTFP)2]+ and [Gd(PyTFP)F]+ respectively. The peak

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at m/z = 189 corresponds to [PyTFP]+. The peaks at m/z = 150, 92 and 65 correspond to decomposition products of the ligand PyTFP. Similarly, for compound 2, the peak at m / z = 776 is corresponds to [Gd(DMOTFP)3]+ as a result of the removal of the pyridine ligand fragment. The detected peaks at m/z = 570 and m/z = 355 can be attributed to the elimination of the first and second heteroalkenolate ligand fragment [Gd(DMOTFP)2]+ and [Gd(DMOTFP)]+ respectively. The base peak detected at m/z = 207 can be assigned to [DMOTFP]+ and m/z = 138 to the [DMOTFPCF3]+.16 Thermogravimetric analysis of Gd(PyTFP)4(PyH) (1) and Gd(DMOTFP)3(Py) (2). The decomposition behavior of 1 and 2 was investigated via thermogravimetric measurements (TG), which showed stepwise mass loss for a crystalline sample (Figure 4). The TG curves of Gd(PyTFP)4(PyH) showed rapid degradation in the range of 39-100°C, which might be due the removal of the lattice pyridine. The relative final residues of 18.47% for 1 is comparable with the theoretical value for the formation of Gd2O3 (17.6%,) indicating the final composition of

the material. Three weight losses

were observed in case of

Gd(DMOTFP)3Py. A mass loss of 9.5% over the range 49–116°C possibly correspond to the loss of one equivalent of pyridine. A further weight loss could be indexed to the decomposition of the DMOFTP ligands, followed by a gradual mass loss up to a remaining weight of the final residues of 22.42%, which is in good agreement with the theoretical value for Gd2O3 (21.2%).

Figure 4: Thermogravimetric profiles of compounds 1 and 2.

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Microwave-assisted synthesis of Gd(OH)3 and their conversion to Gd2O3 NPs. Microwave-assisted synthesis of materials is well suited for high throughput synthesis of nanomaterials.36,37,38,39,40 For this reason, the two Gd-complexes were subjected to the microwave-assisted decomposition experiments to investigate their potential as molecular precursors for Gd-based nanomaterials. The microwave synthesis has been performed by dissolving the targeted compound in a mixture of DMF/H2O, the reaction mixture was then transffered to the microwave vehicle and heated for 10 min. The as-prepared products were amorphous and need to annealed at 800˚C for 2 h in order to induce crystallization. The powder X-ray diffraction revealed a hexagonal phase (P63/m) of Gd(OH)3 with lattice constants a = b = 0.63 nm and c = 0.36 nm (JCPDS card 83-2037) (Figure 5, a and b). EDX analysis provides the existence of Gd and O elements without any additional impurities, Figure S2. Upon thermal treatment, the as-prepared Gd (OH)3 were converted to Gd2O3 nanoparticles as all identified peaks could be indexed to the pure cubic phase of Gd2O3. The high intensity of the diffraction peaks confirmed the crystalline nature of the hydroxide and oxide nanoparticles. The visible broadening of the peaks is an evidence for the small size of the particles according to the Scherrer equation.41

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Figure 5: X-ray diffraction pattern of the obtained Gd(OH)3 and Gd2O3 nanocrystals from microwave synthesis using precursors 1 (a) and 2 (b). The references of Gd(OH)3 (JCPDS C83-2037) in black, and for Gd2O3 (JCPDS C12-0797) in blue.

Irrespective of the chosen precursor, the microwave reactions yielded to a rod-shaped nanomaterial. (Figure 6, a and b) showed an anisotropic growth commonly observed in lanthanide hydroxides.42,43,44

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Figure 6: Scanning electron microscopy (SEM) images of the as-prepared elongated nanostructures obtained from the microwave treatments of precursors 1 (a) and 2 (b).

Transmission electron microscopy (TEM) of the NPs obtained by the decomposition of precursor 1 (Figure 7 b) showed spherical particles with an average size of 17-20 nm after calcination at 800˚C for 2 h. On the other hand, the TEM micrograph of the particles obtained from precursor 2 (Figure 7 c) showed a self-assembly of spherical particles (20 nm).These spherical particles lead to form a pseudo one-dimensional structure through an aggregative mechanism facilitated by alignments of crystalline facets (Figure 7 d). The insets showed a selected area electronic diffraction (SAED) pattern, which demonstrate the crystalline features of as synthesized NPs.

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Figure 7: TEM images of Gd2O3 nanocrystals obtained after calcining products derived from the microwave treatments of precursors 1 (a and b) and 2 (c and d), the insets show the SAED patterns.

Magnetic Measurements. The temperature dependent magnetization data (Figure 8, a) exhibited no significant difference between field cooling and zero field cooling curves, indicating that any blocking temperature is missing. This is possibly due to paramagnetic nature of Gd2O3 since blocking temperatures are observed for superparamagnetic samples. However, there is a difference in the estimated Weiss-constant, which might be correlating with the particle sizes. The estimated paramagnetic moments ranged from 8.1−8.6 µB per Gd3+, which is close to the theoretical value of 7.98 µB.

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Figure 8: (a) Temperature dependent magnetic susceptibility of Gd2O3 nanoparticles with both field cooled (FC) and zero-field cooled (ZFC) curves. The inset displays the inverse susceptibility of the FC curves, where a Curie-Weiss fit has been made to extract the Weiss-constants (ΘCW), (b) Isothermal magnetization (M) as function of applied B-field at 2 and at 300 K. The inset is a magnification of the 300 K data.

The paramagnetic behavior is reflected in the magnetization data of the two samples (Figure 8, b): linear field dependence of the magnetization at room temperature and a saturating moment without remanence at 2 K. Sample 2 (B) is clearly different from sample 1 (A). The former even exhibits saturation closing in on the theoretical 7 µB for a fully polarized J = 7/2 (Gd3+). However, (A) seems to be deviating from paramagnetic behavior, which would indicate completely different particle sizes. Sample A should contain slightly larger particles, which promotes the anti-ferromagnetic interactions in the crystalline grains and causes a lower magnetization as well as a more negative Weiss temperature. A similar situation was explained the same way by others.45 At 300 K, all values are comparable with those reported by Sakai et al.46 corresponding to NPs in the range 18-66 nm. At 1 T, sample (B) behaves similar to the "as prepared" sample (50 emu g-1 at 1 T) of Majeed et al while (A) would correspond to the "annealed" sample (30 emu g-1 at 1 T).47,48 Cytotoxicity assay. The Gd2O3 particles obtained from precursors 1 and 2 were employed to screen their cytoxicity profile for different concentration (5-100 µg/ml) with incubation time of 24 h, using 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay as described before.49 Regardless of all chosen probes, the viability of the cells incubated with the NPs remained above 80% for different particles concentration (5100 µg/ml), which proves their reliable biocompatibility. Figure 9 showed that the viability 13



decreased when the concentration increased, however, there is a slight growth in viability when the concentration of NPs was 100 µg/ml. This could be explained by uncontrolled difference in the density of cells, which is in good agreement with the literature reported about Gd2O3 NPs and their biocompatibility.5,6,50 These results indicated that our particles have no significant toxic effect on the tested cells, which might be attributed to the fact that rigid Gd2O3 nanocrystal matrices disable the leakage of free toxic Gd3+ ion to the contracted cells. Additionaly, due to the agglomerative behavior the particles may show reduced surface area and thereby the cells are exposed, to a lesser extent, to the particles in suspension.

Figure 9: Cell viability profile of cultured HEK293 cells after incubation for 24h with the two samples of Gd2O3 nanocrystals at different concentrations.

Relaxometric characterization of the Gd2O3 nanoprobes. The effectiveness of MRI contrast agent in increasing the relaxation of the surrounding nuclear spins is usually measured in terms of relaxivity. There are some important parameters affecting the relaxation time of the water molecules, e.g. the size of nanocluster, composition, the number of gadolinium ions per nanoparticle, as well as the surface coating.51,52

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Figure 10: Patterns (a) and (c) represent the longitudinal relaxation rates of the resulting Gd2O3 NPs from precursor 1 and 2, respectively, patterns (b) and (d) represent the transverse relaxation rate of the Gd2O3 NPs from precursor 1 and 2, respectively.

Employment of paramagnetic gadolinium oxide NPs significantly increases T1 relaxation time of the surrounding nuclei caused by a large net positive magnetic susceptibility of Gd3+ ion, as a result, the contrast effect can be detected indirectly by virtue of changes in proton relaxation behavior.1 1/. 1/ Gd

(1)

According to equation (1), a plot of the observed relaxation rates 1/. versus the Gd concentration produced a straight line where its slope defines the relaxivity, (in units of mM-1s-1). 1/ corresponded to the relaxation rate of the water nuclei in the absence of a paramagnetic solute. 15



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To evaluate the MRI sensitivity of the Gd2O3 NPs as a T1-contrast agent, the longitudinal and transverse relaxation time of the water proton of the aqueous solutions containing different concentration of Gd3+ ion was measured. As shown in Figure 10 the longitudinal relaxivity ( ) was estimated to be 2.30 s-1mM-1 and 2.40 s-1mM-1, and the transverse relaxivity ( ) was found to be 13.0 s-1mM-1

and 7.0 s-1mM-1

for sample 1 and 2,

respectively. The relaxivity results revealed that is less than anticipated enhancement to water proton relaxation rate. This might be explained by shape effects and strong inter-particles interactions. As a result, agglomerates might be formed. This agglomeration behavior resulted in the precipitation of particles out of the solution, which decrease the overall surface area. This causes an increase in the interaction distance between the particles and the water proton (˃ 0.5 nm), hence lowering the relaxivity effect.53 Conclusion The synthesis and characterization of two new gadolinium heteroalkenolate complexes and their utilization as precursors to produce gadolinium oxide NPs via microwave-assisted method is reported. Comparative analysis of the molecular properties and nanomaterials characterization data shows that crystal chemistry and symmetry have a pronounced influence on the morphology of the resulting nanomaterials. Formation of quasi onedimensional strands of Gd(OH)3 in the microwave assisted decomposition of 1 and 2 is probably driven by the faster growth kinetics of hydroxides in Z-direction. Microstructure of annealed nanostructures showed that despite the phase transformation [Gd(OH)3 to Gd2O3], the anisotropic form remained due to the preferred attachment of Gd2O3 crystallites formed upon calcination. As-synthesized Gd2O3 NPs do not show any pronounced cell toxicity on the cell type chosen, this may also possibly due to not fully dispersed nanomaterial. Increased dispersibility will be performed in future as well as toxicity study using other cell types. The MRI sensitivity was rather low due to the strong agglomeration effects that lower the overall surface area required for relaxation of water molecules. Indeed, the use of stable capping agent to prevent the uncontrollable growth of particles and maximize their dispersibility would be very valuable in the future efforts on these nanomaterials. The prospective efforts will enable us to achieve the acceptable clearance of those blood pool contrast agents from the human body. 16


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Experimental section Synthesis

of

3,3,3-trifluoro-1-(pyridine-2-yl)propen-2-ol

(PyTFP).

3ml

of

2-methylpyridine (30.38 mmol) was dissolved in 12 ml pyridine (148.37 mmol) and 80 ml toluene. 12 ml of trifluoroacetic anhydride (85.13 mmol) was slowly added to the mixture at 0°C. The reaction mixture was stirred at room temperature for 18 h, followed by quenching with 300 ml saturated aqueous Na2CO3 solution and extracting with 4x250 ml ethyl acetate. The organic layer was washed with brine solution and dried over Na2SO4. All volatiles were removed under reduced pressure and the crude product was sublimed (50°C, 10-3 mbar) to yield yellow crystals. 3.92 g (70% of theory).

1

H NMR (300 MHz, 25°C, CDCl3) δ

3

[ppm] = 15.91 (s, 1 H, H-OH), 8.12 (d, JH-H = 5.9 Hz, 1 H, 5-H,), 7.70 (t, 3JH-H = 7.75 Hz, 1 H, 3-H), 7.03 (d, 3JH-H = 6.5 Hz, 1 H, 2-H), 7.03 (t, 3JH-H = 8.5 Hz, 1 H, 4-H), 5.84 (s, 1 H, 6-H).13C NMR (300 MHz, 25°C, CDCl3): δ [ppm] = 163.2 (7-C), 155.7 (1-C), 138.7 (3-C), 139.0 (5-C), 122.5 (2-C), 118.9 (8-C), 118.0 (4-C), 90.1 (6-C). 1

19

F NMR (300 MHz, 25°C,

2

CDCl3) δ [ppm] = –74.6 (s, JF,C = 281.7 Hz, JF,C = 33.2 Hz). Synthesis of 1,1,1-trifluoro-3-[2-(4,5-dimethyloxazolyl)]-propen-2-ol (DMOTFP). A mixture of 2,4,5-trimethyloxazole (40 mmol), pyridine (200 mmol) and 60 ml toluene was cooled to 0 °C, and120 mmol trifluoroacetic anhydride was added in a drop wise. After the complete addition, the reaction mixture was allowed to attain room temperature and stirred for 18 h. The aqueous phase was diluted with Na2CO3 solution and extracted with ethyl acetate (2 X200 ml). The combined organic phases were dried over Na2SO4 and the solvent removed under reduced pressure. After sublimation at (45˚C, 10-3 mbar), 7.3 g (88% of theory) of colorless crystals is obtained as product. 1H NMR (300 MHz, 25°C, CDCl3): δ [ppm] = 2.13 (s, 3H, 5-Me), 2.27(s, 3H, 4-Me), 5.87 (s, 1H, CH), 10.66 (s, ∆1/2 = 8 Hz, 1H, OH). 3

13

C NMR (300 MHz, 25°C, CDCl3): δ [ppm] = 9.70 (s, 4-Me), 9.94 (s, 5-Me), 84.01 (q,

JC,F = 3.5 Hz, CH), 121.13 (q, 1JF,C = 277 Hz, CF3), 126.29 (s, C-4), 141.39 (s, C-5), 156.62

(q, 2JC,F = 35 Hz, COH), 160.12 (s, C-2).

19

F NMR (300 MHz, 25°C, CDCl3) δ [ppm] = –73.3

(s, 1JF,C = 277 Hz, 2JF,C = 35 Hz). Synthesis of gadolinium tris [N,N-bis(trimethylsilyl)amide]. [Gd{N(SiMe3)2}3] was prepared via salt elimination reaction by literature methods using 2.3 g (9.00 mmol) of gadolinium(III) chloride, 5.7 mL (27 mmol) of hexamethyldisilazane, and 11 mL of 2.5 M (27 mmol) n-butyllithium solution in 40 mL of tetrahydrofuran. The mixture was stirred overnight, 17



(16 h) and then the solvent was removed in vacuo. The final product was obtained upon sublimation at 160 ˚C. Synthesis of Gd(PyTFP)4(PyH) (1). 367 mg (2 mmol mole) of 3,3,3-trifluoro-1-(pyridine-2yl)propen-2-ol (PyTFP) and 4 ml pyridine (Py) were added to a 10 ml toluene solution containing 310 mg (0.5 mmol) of Gd[N(SiMe3)2]3. The reaction mixture was stirred overnight at room temperature, followed by removal of the solvent and HMDS under reduced pressure to afford pale yellow solid which is crystallized from toluene. Yield: 370 mg (74%). CHNS Calcd: C, 39.95; N, 5.82; H, 2.10. Found: C, 39.91; N, 5.49; H, 2.41. EI-MS: 721 (100%, M+ − PyTFP), 534 (50%, M+ − PyTFP), 365 (25%, M+ − PyTFP), 189 (40%, PyTFP), 120 (60%, −CF3 ), 92 (70%,−CO). Synthesis of Gd(DMOTFP)3Py (2). 189 mg (0.9 mmol mole) of 1,1,1-trifluoro-3-[2-(4,5dimethyloxazolyl)]-propen-2-ol (DMOTFP) and 4 ml pyridine (Py) were added to a 10 ml toluene solution containing 147 mg (0.23 mmol) of Gd[N(SiMe3)2]3. The reaction mixture was stirred overnight at room temperature, followed by removal of the solvent and HMDS under reduced pressure to afford yellow solid which is crystallized from concentrated toluene. Yield: 160 mg (81%). CHNS Calcd: C, 40.75; N, 6.55; H, 3.07. Found: C,39.98; N,6.09; H,3.05. EI-MS: 776 (100%, M+ − DMOTFP), 570 (25%, M+ − DMOTFP), 360 (20%, M+ − DMOTFP), 207 (80%, DMOTFP), 138 (60%, −CF3), 111 (35%,−CO). Microwave assisted synthesis using precursors 1 and 2. 50 mg of the precursor was dissolved in 3 ml dimethylformamide and 1ml water, the mixture was homogenized by ultrasonication, and transferred to pressure-resistant microwave vessel. The microwave synthesis reaction was performed at 190˚C and 1.7 bar for 10 mints. The microwave power was set to 150 W power. After cooling down, the obtained white precipitate was separated by centrifuge at 9000 rpm and washed three times with water and ethanol and dried overnight at 60˚C. The final nanocrystals were obtained after annealing at 800˚C for 2 h. Cell proliferation assay. The cytotoxicity of the Gd2O3 nanocrystals was evaluated by means of MTT assay, using HEK 293 cells. HEK 293 cells (150 µl of 7.5x104 cells/ml) were cultured in a 96-well plate at 37 °C, 5% CO2 for 24 h. The nanocrystals (200 µl in 2ml sterilized water) were incubated in the medium with different concentration, (5 µg, 10 µg, 20 µg , 50 µg, 100 µg) over a period of 24 and 48 h at 37 °C. HEK 293 cells treated only with culture media fixed as positive control. To each well, MTT (5 mg/ml) was added for 2 h 18


Page 18 of 25

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incubation at 37 °C. Afterwards, the supernatant was removed, and 150 µl DMSO/well were added to resolve the formazan-crystals. The absorbance was measured at 490 nm with reference wavelength of 630 nm using Elisa reader multiplate (ELX 800, BioTek Instruments, USA). Relaxation measurement Relaxation times were measured with a Bruker minispec mq60 NMR analyzer operated at 1.41 T Magnetic field at 40 °C. The Gd(III) concentrations of the samples were determined by inductively coupled plasma mass spectroscopy (ICP-MS). The longitudinal T1 and the transverse T2 relaxation times were measured for various aqueous solutions in different Gd(III) ion concentrations. The inverse relaxation times 1/T1 (R1) and 1/T2 (R2) were then plotted as a function of Gd concentrations, respectively. Materials & Characterizations. Materials. The ligands were synthesized according to the reported procedures.16,17 Anhydrous gadolinium(III) chloride was supplied by Fischer Scientific, hexamethyldisilazane (HMDS), n-butyllithium (2.5 M in hexane), and all reagents, were used as received without further purification. All solvents were dried using typical methods with the suitable desiccating reagents and distilled before use. Characterizations. Elemental analyses were carried out using a HEKAtech CHNS Euro EA 3000. Mass spectra were obtained on a Finnigan MAT 95 (20 eV) in m/z (relative percentage), operating in positive ion modes. NMR spectra were recorded on a Bruker Avance II 300 spectrometer; chemical shifts are quoted in parts per million relative to tetramethylsilane (1H, 300.1 MHz;

13

C, 75.7 MHz) and CCl3F (19F, 282.4 MHz).

Thermogravimetric analysis (TGA) was performed on Netzsch STA 449C Jupiter, samples were characterized in Al2O3 chamber in atmosphere of dry nitrogen or synthetic air (80% N2 + 20% O2), flow: 70 cm3 min-1, heating ramp 10 °C min-1 to 900°C. Data collection for X-ray structure elucidation was performed on a STOE IPDS I/II diffractometer using graphitemonochromated Mo Kα radiation (0.710 73 Å). The programs used in this work are STOE’s X-Area

54

and the WINGX suite of programs,55 including SIR-92,56 and SHELXL-97

57

for

structure solution and refinement. The morphologies and composition of the samples were observed by Transmission electron microscope (TEM) using Zeiss LEO 912 instrument equipped with an LaB6-cathode operated at 120 kV high voltage. Magnetic measurements 19



were

performed

with

a

superconducting

quantum

Page 20 of 25

interference

device

(SQUID)

magnetometer (Quantum Design, MPMS XL-7). ■ ASSOCIATED CONTENT Supporting Information X-ray crystallographic data files in CIF format for compounds Gd(PyTFP)4(PyH) and Gd(DMOTFP)3Py. This material is available free of charge via the Internet at http://pubs.acs.org. ■ AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interest. ■ ACKNOWLEDGMENTS The authors would like to thank the University of Cologne and the “Deutscher Akademischer Austauschdienst” (DAAD) for financial support. Additionally, we are thankful to Dr. L. Czympiel for the fruitful discussion regarding crystal structure, Mr. K. Arroub and Ms. I. Gessner for performing toxicity test, Dr. S. Roitsch for TEM measurements, Mr. V. Vykoukal (Masaryk university, Brno, Czech republic) for TGA characterization, and Mikroanalytisches Laboratorium Kolbe (Mülheim, Germany) for the ICP-MS measurements. Z. Hu and K. Uvdal acknowledges financial support from the Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linköping University (Faculty Grant SFO-Mat-LiU # 2009-00971).

20


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References (1)

Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Chem. Rev. 1999, 99, 2293–2352.

(2)

Lauffer, R. B. Chem. Rev. 1987, 87, 901–927.

(3)

Ahrén, M.; Selegård, L.; Klasson, A.; Söderlind, F.; Abrikossova, N.; Skoglund, C.; Bengtsson, T.; Engström, M.; Käll, P. O.; Uvdal, K. Langmuir 2010, 26, 5753–5762.

(4)

Le Duc, G.; Roux, S.; Paruta-Tuarez, A.; Dufort, S.; Brauer, E.; Marais, A.; Truillet, C.; Sancey, L.; Perriat, P.; Lux, F.; Tillement, O. Cancer Nanotechnol. 2014, 5, 4.

(5)

Zhang, B.; Jin, H.; Li, Y.; Chen, B.; Liu, S.; Shi, D. J. Mater. Chem. 2012, 22, 14494.

(6)

Cho, M.; Sethi, R.; Ananta narayanan, J. S.; Lee, S. S.; Benoit, D. N.; Taheri, N.; Decuzzi, P.; Colvin, V. L. Nanoscale 2014, 6, 13637–13645.

(7)

Ahrén, M.; Selegård, L.; Söderlind, F.; Linares, M.; Kauczor, J.; Norman, P.; Käll, P.; Uvdal, K. J. Nanoparticle Res. 2012, 14, 1006.

(8)

Tian, G.; Gu, Z.; Liu, X.; Zhou, L.; Yin, W.; Yan, L.; Jin, S.; Ren, W.; Xing, G.; Li, S.; Zhao, Y. J. Phys. Chem. C 2011, 115, 23790–23796.

(9)

Söderlind, F.; Pedersen, H.; Petoral, R. M.; Käll, P. O.; Uvdal, K. J. Colloid Interface Sci. 2005, 288, 140–148.

(10)

Liu, Z.; Liu, X.; Yuan, Q.; Dong, K.; Jiang, L.; Li, Z.; Ren, J.; Qu, X. J. Mater. Chem. 2012, 22, 14982.

(11)

Nguyen, T. D.; Do, T. O. J. Phys. Chem. C 2009, 113, 11204–11214.

(12)

Guo, J.; Yang, W.; Wang, C. Adv. Mater. 2013, 25, 5196–5214.

(13)

Veith, M. J. Chem. Soc. Dalt. Trans. 2002, 12, 2405–2412.

(14)

Mathur, S.; Shen, H.; Veith, M. J. Metastable Nanocrystalline Mater. 2004, 20–21, 118–126.

(15)

Revaprasadu, N.; Mlondo, S. N. Pure Appl. Chem. 2006, 78, 1691–1702.

(16)

Giebelhaus, I.; Müller, R.; Tyrra, W.; Pantenburg, I.; Fischer, T.; Mathur, S. Inorganica Chim. Acta 2011, 372, 340–346.

(17)

Brückmann, L.; Tyrra, W.; Stucky, S.; Mathur, S. Inorg. Chem. 2012, 51, 536−542.

(18)

Büyükyazi, M.; Hegemann, C.; Lehnen, T.; Tyrra, W.; Mathur, S. Inorg. Chem. 2014, 53, 10928–10936. 21



Page 22 of 25

(19)

Fornalczyk, G.; Valldor, M.; Mathur, S. Cryst. Growth Des. 2014, 14, 1811–1818.

(20)

Appel, L.; Leduc, J.; Webster, C. L.; Ziller, J. W.; Evans, W. J.; Mathur, S. Angew. Chemie Int. Ed. 2014, 53, 1–6.

(21)

Kim, B. H.; Lee, N.; Kim, H.; An, K.; Park, Y.; Choi, Y.; Shin, K.; Lee, Y.; Kwon, S. G.; Na, H. B.; Park, J.; Ahn, T.; Kim, Y.; Moon, W. K.; Choi, S. H.; Hyeon, T. J. Am. Chem. Soc. 2011, 133, 12624-12631.

(22)

Fortin, M. A.; Petoral, R. M.; Soderlind, F.; Klasson, A.; Engstrom, M.; Veres, T.; Kall, P. O.; Uvdal, K., Nanotechnology 2007, 18.

(23)

Dong, H.; Du, S. R.; Zheng, X. Y.; Lyu, G. M.; Sun, L. D.; Li, L. D.; Zhang, P. Z.; Zhang, C.; Yan, C. H.; Chemical Reviews 2015, 115, 10725-10815.

(24)

Liu, Z.; Liu, X.; Yuan, Q. H.; Dong, K.; Jiang, L. Y.; Li, Z. Q.; Ren, J. S.; Qu, X. G. J. Mater. Chem. 2012, 22, 14982-14990.

(25)

Liang, G.; Cao, L.; Chen, H.; Zhang, Z.; Zhang, S.; Yu, S.; Shen, X.; Kong, J. J. Mater. Chem. B 2013, 1, 629-638.

(26)

Majeed, S.; Shivashankar, S. A.; J. Mater. Chem. B 2014, 2, 5585-5593.

(27)

Niinistö, J.; Petrova, N.; Putkonen, M.; Niinistö, L.; Arstila, K.; Sajavaara, T. J. Cryst. Growth 2005, 285, 191–200.

(28)

Aspinall, H. C.; Gaskell, J.; Williams, P. a.; Jones, A. C.; Chalker, P. R.; Marshall, P. a.; Smith, L. M.; Crichlow, G. W. Chem. Vap. Depos. 2004, 10, 13–17.

(29)

Kukli, K.; Hatanpää, T.; Ritala, M.; Leskelä, M. Chem. Vap. Depos. 2007, 13, 552.

(30)

Hemmer, E.; Kohl, Y.; Colquhoun, V.; Thielecke, H.; Soga, K.; Mathur, S. J. Phys. Chem. B 2010, 114, 4358–4365.

(31)

Baxter, I.; Drake, I. S. R.; Hursthouse, M. B.; Malik, J. K. M. A.; Mcaleese, J.; Otwaytc, I. C. D. J.; Jc, J. C. P. Inorg. Chem. 1995, 6, 1384–1394.

(32)

Monteiro, J. H. S. K.; Adati, R. D.; Davolos, M. R.; Vicenti, J. R. M.; Burrow, R. a. New J. Chem. 2011, 35, 1234–1241.

(33)

Daniel, S. D.; Lehn, J.-S. M.; van der Heide, P.; Wang, Y.; Hoffman, D. M. Inorganica Chim. Acta 2006, 359, 257–260.

(34)

Gao, H.-L.; Jiang, L.; Liu, S.; Shen, H.-Y.; Wang, W.-M.; Cui, J.-Z. Dalt. Trans. 2016, 253–264.

(35)

Gao, F.; Yang, F.-L.; Zhu, G.-Z.; Zhao, Y. Dalt. Trans. 2015, 44, 20232–20241.

(36)

de la Hoz, A’ngel Dı’az-Ortiz, Andre’s Moreno. Chem. Soc. Rev. 2005, 34, 164.

(37)

Bilecka, I.; Niederberger, M. Nanoscale 2010, 2, 1358. 22


546–

Page 23 of 25 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(38)

Ma, L.; Chen, W.-X.; Zhao, J.; Zheng, Y.-F. J. Cryst. Growth 2007, 303, 590–596.

(39)

Xiao, L.; Shen, H.; von Hagen, R.; Pan, J.; Belkoura, L.; Mathur, S. Chem. Commun. (Camb). 2010, 46, 6509–6511.

(40)

Baghbanzadeh, M.; Carbone, L.; Cozzoli, P. D.; Kappe, C. O. Angew. Chemie Int. Ed. 2011, 50, 11312–11359.

(41)

Patterson, a. L. Phys. Rev. 1939, 56, 978–982.

(42)

Wang, X.; Li, Y. Pure Appl. Chem. 2006, 78.

(43)

Xun Wang and Yadong Li. Angew. Chem. Int. Ed 2002, 41, 4790–4793.

(44)

Du, G. H.; Van Tendeloo, G. Nanotechnology 2005, 16, 595–597.

(45)

Correa, E. L.; Santos, B. B.; Cavalcante, F. H. M.; Correa, B. S.; Freitas, R. S.; Carbonari, A. W,; Potiens, M. P. A. AIP Advances 2016, 6, 2158-3226.

(46)

Sakai, N.; Zhu, L.; Kurokawa, a; Takeuchi, H.; Yano, S.; Yanoh, T.; Wada, N.; Taira, S.; Hosokai, Y.; Usui, a; Machida, Y.; Saito, H.; Ichiyanagi, Y. J. Phys. Conf. Ser. 2012, 352, 12008.

(47)

Majeed, S.; Shivashankar, S. a. J. Mater. Chem. B 2014, 2, 5585.

(48)

Issa, B.; Obaidat, I. M.; Albiss, B. A.; Haik, Y.; Int. J. Mol. Sci. 2013, 14, 2126621305.

(49)

Mosmann, T. J. Immunol. Methods 1983, 65, 55–63.

(50)

Park, J. Y.; Baek, M. J.; Choi, E. S.; Woo, S.; Kim, J. H.; Kim, T. J.; Jung, J. C.; Chae, K. S.; Chang, Y.; Lee, G. H. ACS Nano 2009, 3, 3663–3669.

(51)

Xiao, L.; Li, J.; Brougham, D. F.; Fox, E. K.; Feliu, N.; Bushmelev, A.; Mertens, N.; Kiessling, F.; Valldor, M.; Fadeel, B.; Mathur, S. ACS Nano 2011, 5, 6315–6324.

(52)

Xiao, L., Mertens, M., Wortmann, L., Kremer, S., Valldor, M., Lammers, T., Kiessling, F., and Mathur, S. ACS Appl. Mater. Interfaces 2015, 7, 6530–6540.

(53)

McDonald, M. A.; Watkin, K. L. Acad. Radiol. 2006, 13, 421–427.

(54)

X-Area 1.16; Stoe and Cie GmbH: Darmstadt, Germany, 2003.

(55)

Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.

(56)

Altomare, a.; Cascarano, G.; Giacovazzo, C.; Guagliardi, a. J. Appl. Crystallogr. 1993, 26, 343–350.

(57)

Sheldrick, G. M. SHELXL-97, P. for C. S. A. University of Göttingen: Göttingen, Germany, 1997.

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TOC-Synopsis page

Air-Stable Gadolinium Precursors for The Facile Microwave-Assisted Synthesis of Gd2O3 Nano-contrast Agents for Magnetic Resonance Imaging †

†

†

‡

‡

§

Shifaa M.Siribbal , Johannes Schläfer , Shaista Ilyas , Zhangjun Hu , Kajsa Uvdal , Martin Valldor , †,* Sanjay Mathur †

Institute of Inorganic Chemistry, University of Cologne, Greinstraße 6, 50939 Cologne Germany.

§

Max Planck Institute for Chemical Physics of Solids, Nöthnitzer Strasse 40, 01187 Dresden, Germany.

‡

Division of Molecular Surface Physics and Nanoscience, Department of Physics, Chemistry, and Biology (IFM), Linköping University, Linköping 58183 Sweden.

Synopsis: 3+

Two new Gd- trifluoro-ß-heteroarylalkenolates compounds were prepared from a certain Gd source. The crystal structure determination of these complexes elucidated their potential as precursor to produce Gd2O3 nanoparticles in a microwave assisted thermal decomposition reaction. The Gd2O3 nanoparticles

24


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surface properties, biocompatibility and relaxivity measurements indicated their potential for magnetic resonance imaging.

25


Air-Stable Gadolinium Precursors for the Facile Microwave-Assisted

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