Robust thallium(III) complexes with inorganic and organic multidentate ligands

Robust thallium(III) complexes with inorganic and organic multidentate ligands PhD thesis Tamás Fodor Supervisor: Dr. Imre Tóth University of Debrecen Debrecen, 2016 Ezen értekezést a Debreceni Egyetem Természettudományi Doktori Tanács Kémiai Doktori Iskola koordinációs kémiai programja keretében készítettem a Debreceni Egyetem természettudományi doktori (PhD) fokozatának elnyerése céljából. Debrecen, 2016. szeptember 13. a jelölt aláírása Tanúsítom, hogy Fodor Tamás doktorjelölt 2011.- 2016. között a fent megnevezett Doktori Iskola koordinációs kémiai programjának keretében irányításommal végezte munkáját. Az értekezésben foglalt eredményekhez a jelölt önálló alkotó tevékenységével meghatározóan hozzájárult. Az értekezés elfogadását javasolom. Debrecen, 2016. szeptember 13. a témavezető aláírása A doktori értekezés betétlapja Robust thallium(III) complexes with inorganic and organic multidentate ligands Értekezés a doktori (Ph.D.) fokozat megszerzése érdekében a koordinációs kémia tudományágban Írta: Fodor Tamás okleveles vegyész Készült a Debreceni Egyetem Kémiai doktori iskolája (K/2 koordinációs kémia programja) keretében Témavezető: Dr. Tóth Imre A doktori szigorlati bizottság: elnök:: Dr. ………………………… tagok: Dr. ………………………… Dr. ………………………… A doktori szigorlat időpontja: 20… . ……………… … . Az értekezés bírálói: Dr. …..................................... Dr…....................................... Dr. …..................................... A bírálóbizottság: elnök: Dr. …...................................... tagok: Dr. ………………………….. Dr. ………………………….. Dr. ………………………….. Dr. ………………………….. Az értekezés védésének időpontja: 20… . ……………… … . 1. Introduction ................................................................................................................ 4 2. Bibliographic review .................................................................................................. 9 2.1. Thallium chemistry............................................................................................................9 2.2. Polyoxometallates.............................................................................................................12 2.3. Macrocyclic polyamino-polycarboxylate ligands ..........................................................19 3. Experimental section................................................................................................ 22 3.1. Materials and Preparation of Solutions .........................................................................22 3.2.1. pH-potentiometry..................................................................................................... 27 3.2.2. Iodide-selective potentiometry ................................................................................28 3.3. Spectrophotometry...........................................................................................................28 3.4. NMR measurements ........................................................................................................ 29 3.5. Crystal structure analysis................................................................................................ 30 3.6. DFT calculations ..............................................................................................................31 4. Results and Discussion ............................................................................................. 33 4.1. Detailed characterization of [Tl(dota)]–..........................................................................33 4.1.1. X-ray crystal structure.............................................................................................33 4.1.2. Solution structure and mixed-complex formation.................................................39 4.1.3. Studies on the stability and kinetic inertness of [Tl(dota)]– by UV-vis Spectroscopy....................................................................................................................... 44 4.1.5. Solution dynamics study with 13C-NMR ................................................................ 55 4.2. Characterization of [Tl(cdo2a)]+ and its iodido mixed-ligand complex.......................64 4.2.1. Background of ligand choice ...................................................................................64 4.2.2. Dissociation kinetics of [Tl(cdo2a)]+.......................................................................65 4.2.3. Acid-base properties of [Tl(cdo2a)]+.......................................................................66 4.2.4. Investigation of the iodido-mixed ligand complex [Tl(cdo2a)I]............................67 4.2.5. Comparison with a rigidified open-chain complex [Tl(cdtabba)]+.......................69 4.3. Study of the ternary complex formation between [Al(nota)] and F+............................73 4.4. Characterization of [Tl2{B-β-SiW8O30(OH)}2]12–, a newly synthesised thalliumcontaining polyoxometallate...................................................................................................77 4.4.1. X-ray crystal structure.............................................................................................77 4.4.2. Solution structure study...........................................................................................79 4.4.2.1. Simulation of Tl NMR spectra ............................................................................ 81 4.4.3. Solution behavior and overall robustness............................................................... 86 4.4.4. Antibacterial activity................................................................................................ 90 5. Summary................................................................................................................... 99 6. Összefoglaló............................................................................................................. 106 8. Scientific publications of Tamás Fodor.................................................................... 125 9. Acknowledgement.................................................................................................... 130 4 1. Introduction Thallium is the heaviest element in Group 13 of the periodic table, with atomic number 81 and relative atomic mass of 204.38. It was discovered by Sir William Crookes in 1861 during a search for tellurium in sulphuric acid plant residue. The metallic element was named after the bright green colour of its emission line, derived from the greek word „θαλλός” which means „budding twig”. Called the “forgotten element” of the periodic table by some, thallium research cannot be described as either widespread or mainstream. There are few books that deal mostly, or exclusively with inorganic thallium chemistry and the bulk of scientific papers on the subject are from a small number of researchers.1,2,3,4 Indeed to most people, both outside and within the scientific community, the most widely known properties of thallium are its toxicity and its use as poison for rodents and sometimes humans. Ongoing inorganic thallium chemistry is mostly confined to its redox reactions, high-temperature superconductors, metal-metal bonds and coordination chemistry.5,6,7,8,9 The element can be found in the Earth’s crust in 0.1–3 ppm, mostly in sulphide ores. It is widely distributed in nature and has no commercially important source mineral (the few thallium-based minerals such as lorándite (TlAsS2), crookesite ((Cu,Tl,Ag)2Se), and avicennite (Tl2O3) are very rare). This wide distribution can be mostly attributed to Tl+ being able to replace potassium in various minerals.10,11 It is manufactured commercially as a by-product from flue dusts created during the roasting of pyrite ores, in sulphuric acid plants, and from the smelting of lead, zinc, and copper. Elemental thallium is recovered by electrolytic reduction of Tl(I) sulfate solutions. 5 Thallium is used in the optical industry to increase the density and refractive index of glass, or create IR optical elements from TlBr–TlI crystals. In the field of electronics, thallium oxysulfide is used in the socalled ‘Thalofide cell’, which is highly sensitive to low-intensity, longwavelength light and thallium-activated NaI or NaCl crystals are used in some types of scintillation detectors. Thallium-containing alloys are also used as good quality bearings, having a very high resistance to corrosion and low friction coefficients. The only current medical application of thallium is its use in the form of intravenous injections of 201Tl (half-life = 72.9 hours) for myocardial imaging. Thallium is toxic to a variety of life forms, including humans. The biochemical behaviour of Tl+ is similar to that of K+, enabling it to replace potassium to some degree and interfere with K+–dependent biological reactions. The lethal dose of thallium is in the range of 10– 50mg/kg. Compared to (both natural & synthetic) „true” poisons, this means that one needs to absorb quite a lot of thallium for a fatal dose (600 mg for humans). The symptoms appear in 1–5 days and are paresthesia of the extremities, hypersecretion, hair loss, uncontrolled muscle movements, convulsions, delirium, coma and ultimately, death by respiratory failure. The metal accumulates in the body and can be absorbed by ingestion or through the skin and membranes, seemingly regardless of chemical form. The most effective known antidote is colloidal Prussian Blue, (KFe3+[Fe2+(CN)6]·nH2O), acting as an ion exchanger for Tl+ in the intestines and accelerating its elimination. Although it is not an outstanding poison, thallium has garnered considerable infamy. This is in part due to the early (1920 to 1970) use of 12 structure, equilibrium, and kinetics have been reported.31,32,33,34,35Four dinuclear species represented by a general formula [(NC)5Pt– Tl(CN)n−1](n−1)− (n = 1–4) and a trinuclear complex [(NC)5Pt–Tl– Pt(CN)5]3− are shown to form in aqueous solution. These are true equilibrium complexes, their solutions also include the parent complexes Pt(CN)42− and Tl(CN)n3–n (n = 0–4), and can be shifted to either side of the equilibrium by changing cyanide concentration and/or pH in the solution. Multinuclear NMR- (13C, 195Pt, 205Tl), IR-, Raman spectroscopy, Electron Spectroscopy for Chemical Analysis (ESCA), X-ray, and Extended X-ray Absorption Fine Structure (EXAFS) studies confirm direct, short (2.60–2.64 Å) Pt–Tl bonds. The spin-spin coupling pattern is consistent with 4 + 1 + 1 equivalent 13CN− ligands (I = 1/2), respectively and one 195Pt nucleus (natural abundance 33.8%, I = 1/2). The compounds are diamagnetic, and the electronic states and the nature of the Pt–Tl bonds have been elucidated by Density Function Theory (DFT) calculation.36 2.2. Polyoxometallates Polyoxometalates 37 , 38 are polyoxoanions that are composed mainly, or completely of transition elements, distinguishing them from their main group analogues (such as silicates), which are both structurally and chemically distinct. The typically water-soluble polyoxometalates (POMs) are most often highly symmetrical anions with molecular structures incorporating multiple metal centers, the current record being 368. Also known as addenda, these metal centers are mainly transition metals of groups 5 and 6 in high oxidation states, such as W(VI) and 13 V(V). Addenda are octahedrally coordinated to six oxygens, forming MO6 building blocks that are joined by corneror edge- (rarely face-) sharing oxygen atoms in a self–assembly manner. The terminology „polyoxo” is due to the large number of coordinated oxygens, usually present as bridging and terminal oxo ligands. Natural POMs may be found in minerals such as sherwoodite (Ca4.5[AlVIV2VV12O40]·H2O) and mendozavilite (Na(Ca,Mg)2FeIII(PO4)2[PMo11O39](OH,Cl)10·H2O), as well as in the Mo & W storage proteins of Azotobacter vinelandii, which contain ~100 of the respective atoms as individual clusters with 3–8 metal centers.39,40 The polyoxoanions of Group 5 & 6 are traditionally classified as either isopolyanions, which are composed solely of addenda and oxygens, or heteropolyanions which incorporate a number of metallic or nonmetallic heteroatoms. The heteroatom and its coordinated oxygens constitute a heterogroup, which is commonly connected to the surrounding MO6 groups by edges or corners. As the coordination environment of the heteroatom most often defines the structural type of the heteroPOM and virtually any element of the periodic table can serve as a heteroatom, the number of known heteropolyanions is great and continually increasing. Addenda atoms are dominantly octahedrally coordinated and retain either one or two (mutually cis) terminal oxygen atoms that comprise the outermost layer of the POM structure in nearly all cases. The first POMs were described by Berzelius41 in 1826 (yellow ammonium–12– molybdophosphate and –arsenate, and their reduced „blue” derivatives), but detailed reports on the chemistry of many polymolybdates and polytungstates only began to emerge in the late 19th 14 century. Keggin introduced the use of X-ray diffraction into POM chemistry in 1933, investigating the structure of H3[(PO4)W12O36]·6H2O.41 The formation of polyoxoanions from mononuclear oxoanions is driven by acidic condensation of MO6 octahedra, resulting in the kinetic and eventually the thermodynamic products under the formation conditions. (Polytungstates and some polyvanadates usually equilibrate much more slowly than molybdates). This also means that all polyoxoanions undergo dissociation in alkaline media. The required pH may, at times, not be achievable in aqueous solutions though. The expected initial step in the polymerization of a tetrahedral oxoanion is condensation of the monoprotonated version. This is the case for V(V) and Cr(VI) but not for Mo(VI) and W(VI). That V, Mo, and W can generate an extensive chemistry of large POMs is a result of their ability to coordinate a largely variable amount of oxygen atoms (4 – 7) (one may mention that Cr cannot). 15 Figure 2.2.1 Examples of POM structures. (a) α-[(PO4)W12O36]3− (Keggin). (b) [(TeVIO6)W6O18]6−, [{CrIII(OH)6}Mo6O18]3− (Anderson– Evans). (c) [(UIVO8)W10O28]8− (Weakley–Yamase). (d) [(CeIVO12)Mo12O30]8− (Dexter–Silverton). (e) α-[(AsO4)2Mo18O54]6− (Wells–Dawson) 16 Several parameters such as pH, temperature, ionic strength, concentration and ratio of reagents greatly influence the resulting POM structures and can be „tuned” to provide a large variety of polyanions. As mentioned, polyanions are formed by self–assembly and in the formation of heteroPOMs, the heterogroup functions as an important template. Closed-shell POMs have low surface–oxygen basicity, making them chemically inert towards electrophiles, and are also known as plenary structures. They usually only react with metal ions in terms of ion pair formation. The Keggin structure (XW12) has become the symbol of POM chemistry and most published research in this field deals with these type of polyanions. Keggin anions may form many structural isomers, of which the best known are those of C3v symmetry, designated β, in which one of the four equivalent edge-shared M3O13 triads found in the original „α” Keggin anion of Td symmetry, is rotated by 60°. Each triad corresponds to three edge–shared MO6 octahedra, which are corner– linked by μ4–oxo bridges to the central heteroatom. Two, three, and all four edge-shared groups, when rotated, produce γ, δ, and ε structures, respectively.42 Each additional rotation destabilizes the Keggin ion, as the number of edge–shared MO6 connections is increased. Figure 2.2.2 Structural isomers of XM12O40n– Keggin anions 17 The number of possible isomers greatly increases in „mixed-addenda” POMs, such as [(PO4)V2W10O36]5−, which has five „positional” isomers of α configuration, and 13 β–isomers. The existence of these isomer types has been well established by NMR spectroscopy. The so-called lacunary, or vacant derivatives of certain polyanions, notably the Keggin and Wells–Dawson structures, are also known. These structures can be prepared by controlled basic hydrolysis and are markedly more reactive than their parent POMs. For heteropolytungstates, loss of W–centers along with their terminal oxoligands leads to structures with varying vacant site numbers (mono– to hexavacant) (e.g. [GeW11O39]7–, [γ-SiW10O36]8–, [P2W15O56]12–, [H2P2W12O48]12–). Figure 2.2.3 Some lacunary anion structures. (a) [(PO4)W11O35]7−. (b) [(PO4)W9O30]9−. (c) [(PO4)2W15O48]14− 18 The removal of each cationic (WO)4+ unit also negates some of the mentioned inertness, as the overall negative charge of the resulting lacunary POM is raised, also increasing nucleophilicity and thus, reactivity. Such vacant POMs are, in essence, inorganic multidentate ligands and may be modified by incorporating additional heteroatoms or –groups into the vacant sites. Figure 2.2.4 Two lacunary POM sandwich type structures (a) [UIV(SiW11O39)2]12−; (b) [PdII2(PW11O39)2]10− and one substituted lacunary POM (c) [Mo7O24{Os(dmso)3}]3−.43 These secondary heteroatoms, depending on their inherent coordination geometry, may reconstruct the original POM structure (such as a Keggin anion), or they may be sandwiched between two lacunary POMs. The POMs, being a large and highly diverse group of compounds, are applied in a wide variety of fields.44,45,46,47 One of the earliest uses is 19 in analytical chemistry: trace–level colorimetric determination of elements that are prone to Keggin–anion formation, namely silicates and phosphates. Phosphotungstic acid (H3PW12O40) is a general stain for electron microscopy. More recent organic derivatives allow highly selective, targeted imaging applications. 48 POMs have proven to be successful phasing agents in the structural crystallography of several large biomolecules, the most noteworthy recent case being [P2W18O62]6– used for the high-res structure of ribosomes (2009 Chemistry Nobel Prize). POMs also find use as industrial–grade catalysts:49 , 50 , 51 , 52 , 53 molybdophosphates in the oxidation of methacrolein to methacrylic acid; tungstophosphoric acids in the production of hydroxoalkanes via alkene hydration; molybdovanadophosphates in alkene oxidation and aromatic coupling, etc. POMs are also breaking ground into medicine, as many of them are biologically active 54 : smaller vanadates and molybdates selectively inhibit enzyme function55 and many polytungstates have been found to possess antitumoral, antibacterial and antiviral activity.56,57,58 2.3. Macrocyclic polyamino-polycarboxylate ligands Macrocyclic amino-carboxylate ligands are widely used in clinical chemistry including medical diagnosis and therapeutic applications involving metal complexes. The ligands consisting of polyazamacrocyclic rings and pendant arms show high selectivity if the size of the ring and the radius of the metal ion match perfectly. Moreover, the nature of the pendant arm attached to the N-atoms of the macrocycle can be used to tune the physico-chemical properties (stability and selectivity) of the metal complexes. In case of bifunctional ligands, there is also a 20 conjugated biological vector (peptide, antibody etc.), i.e. a covalently bonded entity in the molecule, responsible for the selective targeting of the complexes in living organisms.59 The most widely studied complexes are the MRI-contrast agents, where the macrocyclic ligands are often the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (dota) and its derivatives, known as the most versatile ligands for medical imaging applications. 60 With a suitably sized cavity and four potentially coordinating pendant arms, this macrocyclic ligand forms complexes with many cations (i.e., Ln3+ ions, Sc3+,61 Y3+,62 Ga3+,63 Bi3+,64 Ca2+,65 Sr2+,66 Zn2+,67 and transition metal ions such as Fe3+,68 Co2+,63 Ni2+, and Cu2+).69 The complexes are usually thermodynamically very stable 70 and kinetically quite inert.71,72 These behaviors together make dota a very safe metal-binder because it can carry the metal component in biological fluids without risk of decomplexation, which would result in uncontrolled distribution of the components (i.e., metal ion and ligand) in the biological system and may cause toxic effects or a decrease in the signal (e.g., relaxivity, luminescence, radioactivity). The advantages of providing high stability and inertness (often called kinetic stability in medical papers) are partly counterbalanced by the slow formation of metal−dota complexes.73 While this is hardly a technical problem for stable metal ions, the long formulation time could be a crucial point for short-lived radioisotopes.74 Very intensive research during the last 2 to 3 decades has produced a trove of chemical knowledge about dota complexes, i.e., the stability constants, formation and dissociation kinetics, and structure in both the solid state and solution have been explored for many metal ions.75 A significant portion of the information that has allowed general conclusions to be established 21 regarding dota complexes has been collected in lanthanide(III)−dota systems, particularly the Gd3+ complex. This is related to the fact that [Gd(dota)]− is a very good and safe general (nonselective) magnetic resonance imaging (MRI) contrast agent (CA) widely used in clinical practice under the trade name Dotarem. Dota complexes are also of great importance in other diagnostic fields, such as radiology (Single Photon Emission Computed Tomography, SPECT and Positron Emission Tomography, PET). The use of macrocyclic complexes, such as dotaderivatives for targeted radioisotope delivery is a relatively fresh and heavily investigated field. One example is Dota-octreotate, an amide of dota and (Tyr3)-octreotate which binds to somatostatin receptors and is therefore selective towards a number of neuroendocrine tumors. Radionuclides commonly transported with DOTATATE (trade name) are 68Ga for tumor diagnosis with PET 76 and 177Lu for ß-radiation treatment.77 It was also reported recently, that macrocyclic metal complexes may be used to bind and deliver certain radioisotopes in anionic form: Al(III)-complexes of peptide-linked amide derivatives of 1,4,7triazacyclononane-1,4,7-triacetate (nota) were shown to bind the PET isotope 18F with promising in vivo results.78,79. This type of radionuclide transport also foregoes bonding the isotope to the backbone of the carrier molecule and most complications associated with the process. It is therefore quite tolerant of low half-life isotopes and allows virtually any modification to the ligand to take place before labeling, such as linkage of a targeting vector. 28 avoid KClO4 precipitation in the membrane. The pH-meter was calibrated with KH-phthalate (pH = 4.005) and KH2PO4-Na2HPO4 (pH = 6.865) buffers and the H+ concentrations were calculated from the measured pH values by applying the method proposed by Irving et al.82 3.2.2. Iodide-selective potentiometry Free iodide concentrations were measured using a Metrohm 6.0502.160 iodide–selective electrode with an Ag/AgCl electrode as reference. As previously stated, electrolytes containing K+ were replaced with 1M NaCl. Measurements were performed at 25 (±0.1) °C, in 1M NaClO4 under a constant argon stream. Calibration of the electrode was performed by titrating a blank 1 M NaClO4 solution with NaI. 3.3. Spectrophotometry UV-VIS spectra were recorded in quartz cuvettes ranging from 1.0 mm to 1.0 cm path length with a Varian Cary 1E UV-Visible Spectrophotometer at 25 °C in the wavelength range 350-200 nm, with data points every 0.5 nm and a scan rate of 100 nm/min, unless otherwise stated. Short-term dissociation kinetics was followed by repeated recordings of spectra, with delay times of 1 hour. The UV-light was cut off from the sample during the delays to avoid photochemical decomposition. Long-term kinetics were followed by separate recordings, with delay times of 1 day or 1 week. 29 3.4. NMR measurements 1H and 13C spectra were recorded with a Bruker DRX 400 spectrometer at 400.1 MHz and 100.6 MHz, respectively. In spite of lacking matching NMR probes capable of 205Tl-measurement, thallium spectra were obtained with a Bruker AM 360 spectrometer by inserting a 500 MHz BB probe and tuning the x-channel to the frequency of 205Tl (207.8 MHz). This setup does not interact with 1H or 2H and does not enable locking or 1H-decoupling to be used. Probe temperatures were kept at 25 (±0.1) °C if not stated otherwise. Calibration was performed using the signal of D2O (4.79 ppm) for 1H-spectra, tetramethylsilane (0 ppm) for 13C-spectra and with 50 mM Tl(I)- and Tl(III)-perchlorate solutions (Tl+: -4.72 ppm, Tl3+: 2039 ppm) for 205Tl-spectra. Line-shape analysis was carried out with a home-made program written in MatLab, using the algorithm developed by Reeves and Shaw. 83 This program fits a signal-shape function simulating the change of coupling-free NMR signals caused by chemical exchange, using modified Bloch-equations (the coupling-free approximation implies that the same exchange rate is applied to both sets of signals). The relative position of the two doublet signals used for the analysis were fixed, while the integrals (populations) and the line widths within the doublets were assumed to be identical. Five parameters were estimated: two to define the baseline, one for the intensity, the frequency specific to the position of the signal and the exchange rate constant. The calculated rate constants were then fitted to the Eyring-Polanyi equation [ln(k/T) = -H/RT + ln(kB/h) + S/R, where k is the rate constant, T is 30 the absolute temperature, kB is the Boltzmann constant, R is the ideal gas constant, h is the Planck constant and H and S are activation enthalpy and activation entropy. 376.5 MHz 19F NMR spectra were collected using a Bruker DRX 400 NMR spectrometer. Calibration was performed with 10 mM slightly basic NaF for 19F spectra (0 ppm). 3.5. Crystal structure analysis The sodium salt of [Tl(dota)] could not be crystallized in spite of repeated trials. Thus, we used the guanidine cation, which is known to aid the preparation of single crystals due to its strong ability to form hydrogen bonds.84 Single crystals of C(NH2)3[Tl(dota)]·H2O could be grown at the interface between 96% ethanol and a solution prepared by method (c) described above. Diffraction intensity data collection was carried out at 293(2) K on a Bruker-Nonius MACH3 diffractometer equipped with a point detector using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). The structure was solved with the SIR-92 program85 and refined by the fullmatrix least-squares method on F2. All non-hydrogen atoms were refined with anisotropic thermal parameters using the SHELXL-97 package.86 Hydrogen atoms were located geometrically and refined in the rigid mode, except for hydrogen atoms of water molecules, which could be found in the difference electron density map. The remaining electron density peaks were found close to the Tl atom. Crystal data and structure refinement details: Formula: C17H32N7O9Tl; MW: 682.87; crystal system: triclinic; space group: P-1; a = 7.498(10) Å; b = 12.406(5) Å; c = 31 12.800(4) Å;  = 91.01(1)º;  = 90.86(4)º; γ = 107.31(6)º; V = 1136.3(16) Å3; Z = 2; Dcalc = 1.996 g cm–3; F(000) = 672; μ = 7.17 mm–1; Reflections collected: 4909; Unique reflections with I > 2(I): 4117; Parameters refined: 331; GOF on F2 = 1.09; R[F2 > 2σ(F2)] = 0.057; Rint = 0.046; wR(F2) = 0.156;   max and   min = 3.58 and –4.05 e Å–3. 3.6. DFT calculations All calculations were performed in aqueous solution employing DFT within the hybrid GGA approximation with the B3LYP exchangecorrelation functional87 and the Gaussian 09 package (Revision B.01).88 Full geometry optimizations of the [Tl(dota)]- system were performed in aqueous solution without symmetry constraints. In these calculations we used the relativistic effective core potential (RECP) of Ross. et al for Tl (CRENBL), which includes 68 electrons in the core, with the valence space (5d, 6s and 6p) represented by an uncontracted (3s3p4d) basis set.89 The ligand atoms were described using the standard 6-311+G(d,p) basis set. The stationary points found on the potential energy surfaces as a result of geometry optimizations were tested to represent energy minima rather than saddle points via frequency analysis. The relative free energies of the different conformations of [Tl(dota)]- complexes were calculated in aqueous solution at the B3LYP/CRENBL/6-311+G(d,p) level, and they include non-potentialenergy contributions (zero point energies and thermal terms) obtained through frequency analysis. The arm rotation and ring inversion processes of [Tl(dota)]- were investigated by means of the synchronous transitguided quasi-Newton method at the B3LYP/CRENBL/6-31+G(d,p) 32 level.90 The nature of the saddle points (one imaginary frequency) was characterized by frequency analysis. The free energy barriers calculated include non-potential energy contributions obtained by frequency analysis. The NMR shielding tensors of the [Tl(dota)]- system were calculated in aqueous solution using the B3LYP functional and the GIAO method.91 In these calculations the more extended 6-311G+(d,p) basis set was used for the ligand atoms. For 13C-NMR chemical shift calculation purposes the NMR shielding tensors of TMS were calculated at the same level. Throughout this work solvent effects were included by using the polarizable continuum model (PCM), in which the solute cavity is built as an envelope of spheres centered on atoms or atomic groups with appropriate radii. In particular, we used the integral equation formalism (IEFPCM) variant as implemented in Gaussian 09.92 The default values for the integration grid (75 radial shells and 302 angular points) and the SCF energy convergence criteria (10-8) were used in all calculations. 33 4. Results and Discussion 4.1. Detailed characterization of [Tl(dota)]– 4.1.1. X-ray crystal structure Crystals of C(NH2)3[Tl(dota)]·H2O contain the [Tl(dota)]- complex, a guanidinium cation and a water molecule. A view of the structure of the complex and bond distances of the metal coordination environment is provided in Figure 4.1.1.1. The Tl3+ ion is directly coordinated to the eight donor atoms of the ligand, with the metal coordination environment being best described as twisted square antiprismatic (TSAP). The stereochemistry of eightand nine-coordinate metal complexes of dota is well documented; the coordination of the ligand to the metal ion introduced two sources of chirality, one associated to the conformation of the cyclen moiety [() or ()], and another related to the layout of the four acetate pendant arms [represented as  or ]. The combination of these two sources of helicity gives rise to four possible stereoisomers existing as two diastereoisomeric pairs of enantiomers. These enantiomeric pairs provide either a square antiprismatic [SAP, ()/()] or a TSAP [()/()] coordination around the metal ion.16e, 93 Inspection of the structure of C(NH2)3[Tl(dota)]·H2O shows that crystals contain the ()/() enantiomeric pair, the two enantiomers being centrosymmetrically related in accordance with the centro-symmetric character of the space group P-1. Both the guanidinium cations and the water 34 molecules are involved in hydrogen-bonding interactions with the oxygen atoms of the acetate groups of the ligand. Figure 4.1.1.1 View of the structure of the [Tl(dota)]- complex present in crystals of C(NH2)3[Tl(dota)]·H2O. The ORTEP plot is at the 30% probability level. Bond distances (Å): Tl01-N1, 2.454(8); Tl01-N4, 2.497(9); Tl1-N7, 2.443(8); Tl01-N10, 2.458(9); Tl01-O1, 2.322(8); Tl01-O11, 2.438(8); Tl01-O41, 2.383(8); Tl01-O71, 2.316(7) 35 Table 4.1.1.1 Structural parameters observed for selected [M(dota)(H2O)]- and [M(dota)]- complexes in the solid state. M La Gd Bi Sc Tm Tl Ionic radius / Åa 1.216 1.107 1.17 0.87 0.994 0.98 M-O / Åb 2.467 2.368 2.538 2.150 2.279 2.365 M-N / Å 2.770 2.663 2.526 2.441 2.529 2.464 M-O / M-N 0.89 0.89 1.00 0.88 0.90 0.96 M-QO / Åc 0.728 0.715 1.112 1.007 1.064 1.252 M-QN / Åd 1.810 1.632 1.434 1.327 1.466 1.324 QO-QN 2.54 2.35 2.55 2.33 2.53 2.58 Twist Angle / ºe 23.2 38.5 25.9 41.1 24.4 25.4 Isomer TSAP SAP TSAP’ SAP’ TSAP’ TSAP’ a Ionic radii for coordination number 8 (Bi, Sc, Tm and Tl) or coordination number 9 (La and Gd) taken from reference 94. b Average bond distances between the metal ion and the O atoms of the acetate arms. c Distance between the metal ion and the least squares plane defined by the coordinated O atoms of acetate groups. d Distance between the metal ion and the least squares plane defined by the N atoms of the macrocycle. e Calculated as the average value of the four torsion angles N-CN-CO-O, where N and O are the donor atoms defining a fivemembered chelate ring and CN and CO represent the centroids of the QN and QO planes, respectively. 36 Figure 4.1.1.2 Variation of the M-N and M-O bond distances with the ionic radius in [M(dota)]- (M = Tm, Sc, Bi or Tl) and [Ca(dota)]2complexes. The solid lines are the linear fits of the data reported for the Ca2+, Sc3+ and Tm3+ complexes (see text) Dota-like complexes with the light Ln3+ ions are usually ninecoordinated, where the ligand acts as eight-dentate and one water molecule is in the inner coordination sphere. Eight-coordination with the absence of a coordinated water molecule is typical for the heavier Ln3+ ions such as Tm3+. In both sub-groups SAP (Ln= Pr, Nd, Sm, Dy) and 37 TSAP (Ln= Ce, Tm) geometries are found. Eight coordinate complexes that lack the apical water molecule are often labeled as SA’ and TSAP’ to differentiate them from the nine-coordinate SAP and TSAP complexes.63a [Sc(dota)]- adopts a SAP' geometry,63a in contrast with the TSAP' coordination observed for [Ca(dota)]2-, [Bi(dota)]- and [Tm(dota)]-.63a,65,66 In [Tl(dota)]- the coordination geometry around Tl3+ is TSAP’. The distinctive structural feature that discriminates SAP and SAP' versus TSAP and TSAP' structures is represented by the twist angle between the two square planes of the antiprism, the basal plane comprised of the four nitrogen atoms of the macrocycle, and the upper plane containing the four coordinated oxygen atoms of the pendant arms. The average twist angle observed for [Tm(dota)]- (25.4º) is close to that expected for a regular twisted square antitiprism (22.5º) and also similar to those found for other complexes having TSAP or TSAP’ structures (Table 4.1.1.1). Table 4.1.1.1 provides a comparison of structural parameters reported in the literature for [M(dota)]- complexes (M = Sc3+,63a Tm3+,63a and Bi3+,65) with those of the Tl3+ analogue. Additionally, we have also included the corresponding data for selected [M(dota)(H2O)]- complexes, with M = La95 or Gd69 as representative members of the earlier and middle members of the lanthanide series, respectively. The average M-O bond lengths are in the range of 2.54-2.15 Å, while the M-N distances range between 2.44 and 2.77 Å. The distances between the virtual planes defined by the four N atoms of the macrocycle (QN) and the four donor oxygen atoms of the pendant arms (QO) are ca. 2.53-2.58 Å for the complexes with TSAP and TSAP’ coordination and 2.33-2.35 Å for those with SAP and SAP’ geometries. Thus, the QO-QN distances for a given coordination polyhedron remain nearly unaffected by the nature of the 44 fast cyanide exchange at high pH values required for the formation of the mixed ligand complex. 4.1.3. Studies on the stability and kinetic inertness of [Tl(dota)]– by UV-vis Spectroscopy The stability constant of [Tl(edta)]– has been determined by a competition method using large excess of both halide ligands and H+.105 In case of [Tl(dota)]– an even greater stability is expected furthermore the macrocyclic complex forms very slowly in acidic solutions, which prevents the use of direct potentiometry for stability constant determination. Instead, we have used a competition method in which both a halide, namely the bromide, and H+ compete for Tl3+ and dota4–, respectively, according to the following equilibrium characterized by the equilibrium constant, Kcomp: (n-1)H+ + [HTl(dota)] + 4 Br–TlBr4– + Hndota(4-n)– (4.1.3.1) Kcomp = [TlBr4–][Hndota(4-n) –]/[HTl(dota)][H+]n-1[Br–]4 (4.1.3.2) Tl3+ behaves as a “soft” acid according to the classification of Pearson, as the stability of halide complexes increases from the light halide ions to the heavy ones. Therefore, iodide would be the strongest competing agent for Tl3+. 45 Figure 4.1.3.1 Time dependence of UV-spectra attributed to the ligandexchange reaction between [HTl(dota)] and Brin 1M HClO4: [HTl(dota)] (red, recorded at t0) is slowly converted to [Tl(Br)4] (blue, recorded at 450 hours; the absorbance value and the shape of the spectrum are in accordance with separate measurements of [TlBr4]). Intermediate spectra were recorded at 1 hour intervals for 19 hours. Conversion is ~99% at 240 h (magenta). However one has to consider redox reactions, i.e. Tl3+ can oxidize iodide to iodine while Tl+ is formed (TlI4– is the only TlIn+3-n species detected in solution at high I–/ Tl3+ ratios).3 Preliminary experiments have confirmed the immediate formation of iodine, and therefore we have selected Brfor the competition reactions. 46 Knowing the kinetic inertness of [M(dota)] complexes, suitable thermodynamic data can only be extracted from properly equilibrated competition systems. Thus, batch samples containing 0.5 mM Tl(dota)–, 0.5 M NaBr were prepared, varying the concentration of the acid in the range of 0.1, 0.3, 0.5, 0.8 and 1M of HClO4 and keeping the total perchlorate concentration constant (at 1M with (Na++H+)ClO4). The dissociation of the complex, i.e. the formation of [TlBr4]– was followed over time recording spectra in the 200-350 nm range until the expected equilibration of the system (Figure 4.1.3.1). The spectra shown in Figure 4.1.3.1 clearly show isosbestic point(s), which is in agreement with the presence of two species ([HTl(dota)] and [Tl(Br)4]) in equilibrium with measurable absorbance during the 240 hours experimental time in the system, in accordance with the equation 4.1.3.1. However, the reaction is substantially slower in the less acidic samples, where the isosbestic points were not observed. This indicates that some kind of parallel side reaction is occurring under these conditions. This may be a slow redox reaction involving bromide ions and the Tl3+ ion in an out-of-cage intermediate in which the metal ion is coordinated only by carboxylate groups (as in the formation/dissociation intermediate observed for other dota complexes). We invested a high amount of time and energy trying to avoid this complication (exclusion of air from samples with argon, increasing temperature to shorten the equilibration time by conventional means and by using a microwave reactor) without any success in measuring the equilibrium constant defined by equation 4.1.3.2. Finally we decided to only use spectra recorded at low conversion to evaluate the kinetics of our Tl-macrocyclic complex by means of the 47 initial rate method. Assuming that [Tl(dota)] dissociates similarly to [Gd(dota)],73c the following equations may be used to evaluate the kinetic data: –d[Tl(dota)]t/dt = kobs[HTl(dota)]t (4.1.3.3) kobs = k0 + k1[H+] + k2[H+]2 (4.1.3.4) where kobs is the observed pseudo first-order reaction rate constant, k0 is the rate constant of spontaneous (or water assisted) dissociation of the monoprotonated complex, k1 and k2 are the constants of proton-assisted dissociation. The experimental results are shown on Figure 4.1.3.2. Curve fitting gives k0 = 0 (fixed to 0 as the fitting of the dissociation kinetic data in a trial returned a small negative value with large error), k1 = (9±7)10–7 s–1M–1 and k2 = (5±0.8)10–6 s–1M–2 values. The data shows quadratic dependence of kobs on acidity with no detectable spontaneous dissociation, which is not surprising because spontaneous dissociation of the monoprotonated complex is expected to occur slower by several orders of magnitude, than the acid-catalyzed dissociation (which is the dominant reaction pathway in the acid concentration range applied in the current study). The k1 value also has a large uncertainty, and may be a calculation artifact caused by the limited number of data points and their inaccuracy in the lower cH+ range related to the above-mentioned side reactions during the very slow competition reaction. This kind of rate law is in accordance with the related literature of dota-complexes, i.e. the dissociation is a dominantly proton-assisted process. (We have found some minor spectral changes that might be related to some interaction 48 between [HTl(dota)] and the Br ion, but we could not quantitatively measure this probably small contribution to the dissociation kinetics). Figure 4.1.3.2 Plot of kobs vs. acid concentration in Tl(III) - dota4 - H+ - Br system Using the kobs = k1[H+] + k2[H+]2 rate law one can calculate the half life of the complex at different pH values. Half-life of [Tl(dota)] is 32 h in 1 M HClO4 and approximated to 5▪109 h at pH = 7.4. The latter value indicates that the dissociation of [Tl(dota)] at physiological pH is negligible. To our surprise however, the [201Tl(dota)] complex was found recently to decompose in vivo.104 Our data suggests that this phenomenon is more likely to be caused by the bioreduction of Tl(III) in the samples 49 rather than the dissociation of the [Tl(dota)] complex. Tl+ (showing similarity to K+ both in size and complexation properties) likely forms a weak and labile complex with DOTA, making the dissociation of the reduced radioisotope from the complex easy. 4.1.4. Additional solution structure data obtained by 1H and 13CNMR spectroscopy The 1H-NMR spectrum of [Tl(dota)] presents six broad signals at room temperature: one doublet can be assigned to the protons of the acetate methylene groups and two doublets to those of the ring (3J1H-205Tl scalar coupling splits these signals into doublets). The broadness of these signals is related to exchange processes occurring in solution. Based on the composition of the complex and that of the solution, the exchange is attributed to the intramolecular rearrangement of the complex. At higher temperatures the signals sharpen and their structure becomes visible as a consequence of the acceleration of the exchange processes. This is also supported by 13C-NMR spectra, which at high temperatures show two signals in the aliphatic region: a singlet assignable to the acetate methylene carbons and a 205Tl coupled doublet of the ring carbons (Figure 4.1.4.1). The carbon nuclei of the methylene groups of the pendant arms do not show 205Tl–coupling. This is likely caused by the combined effect of a two-bond coupling (through the nitrogen) and a three-bond coupling (through the carboxylate oxygen). These couplings may possess differing signs that presumably cancel out. The 1Hand 13C-NMR spectra recorded at low temperature (272 K) are relatively well resolved, and could be fully assigned with the aid of 50 the homonuclear 1H-1H COSY and heteronuclear 1H-13C HSQC spectra (Figure 4.1.4.2, see Chart 4.1.4.1 for labeling). At this temperature the ring carbon doublet splits into two, indicating the presence of two different chemical environments for the carbon nuclei of the macrocyclic moiety. Figure 4.1.4.1 100 MHz 13C-NMR spectra of a 0.1 M Na[Tl(dota)] solution in D2O recorded at different temperatures in D2O (pH = 4) The spectrum shows four signals: the 205Tl-coupled doublet (2J205Tl-13C = 64 Hz) of the carboxylate (-C=O) groups at δ=179.7 ppm (C1), a singlet due to the -CH2groups of the acetate pendant arms at 58.8 ppm (C2), and two 205Tl-coupled doublets of the non-equivalent carbon 51 atoms of the macrocycle ring centered at δ=49.2 (2J205Tl-13C = 156 Hz) and 53.6 (2J205Tl-13C = 161 Hz) ppm. This pattern points to a C4 symmetry of the [Tl(dota)] complex at low temperatures, while the spectra at temperatures higher than Figure 4.1.4.2 400 MHz 1H-1H COSY spectrum of 0.1 M [Tl(dota)] recorded in D2O solution (pDreading = 4) at 272.5 K (see Chart 4.1.4.1 for labelling) 52 NN N N COO - COO- -OOC -OOC 1 2 3 4 Chart 4.1.4.1 Ligand H4dota and the numbering scheme used for NMR spectral assignment Figure 4.1.4.3 400 MHz 1H-13C HSQC spectrum of 0.1 M [Tl(dota)] at 272.5 K 53 320 K can be interpreted as an effective C4v symmetry. The 1H-13C HSQC spectrum (Figure 4.1.4.1) shows that each of the 3 carbon nuclei in the aliphatic region is coupled with 4 proton signals, two of them showing very small chemical shift differences. This is clearly observed for the proton nuclei of the –CH2– groups of the acetate arms (H2). For these protons one expects an AB spin system with a 2Jax-eq of ~16 Hz. However, the coordination of the ligand to the Tl3+ ion creates an AB-X system, which splits each of the components of the AB spin systems into doublets due to the 3J1H-205Tl coupling. The 1H–1H COSY spectrum relates the signals at 3.19 ppm and 3.68, and those at 3.16 and 2.24 ppm, while no cross-peak is observed relating the signals at 3.68 and 2.24 ppm. All these four signals are however correlated to the carbon atom of the acetate arms in the HSQC spectrum. Thus, the signals at 3.68 and 2.24 ppm are attributed to a single proton nucleus whose resonance is split by the coupling to 205Tl. An analogous reasoning allowed us to assign the proton signals of the macrocyclic fragment (Table 4.1.4.1). Furthermore, the spin pattern of the signals allowed us to discriminate between axial (ax) and equatorial (eq) proton nuclei. Indeed, the different H-C-C-H dihedral angles relating axial and equatorial protons with the protons at a three bond distance result in different coupling patterns, as expected by the Karplus relationship.106,107 As a result, the equatorial protons provide small 3J coupling constants, so that their coupling patterns are dominated by the strong 2Jeq-ax coupling (~16 Hz). This is for instance the case of the signal at 2.00 ppm, which is observed as a pseudo-doublet. On the contrary, axial protons give two strong couplings (2Jax-eq and 3Jax-ax) and a weak one 60 Since the temperature dependence of the signals at 53.6 and 49.2 ppm covers both the fast exchange and the slow exchange regimes, we used these resonances to perform a quantitative band-shape analysis of the exchange process, which provides the exchange rates kexch at every temperature. The agreement between the experimental and simulated spectra is excellent (Figure 4.1.5.2). The temperature dependence of the evaluated time constants was subsequently used to obtain the activation parameters for the exchange process using the Eyring-Polányi equation. The results are compared to those obtained for related dota4 complexes in Table 4.1.5.1. Table 4.1.5.1 Activation parameters obtained for the ()  () interconversion in [Tl(dota)]  and related systems H (kJ mol1) S (J K1 mol-1) G298 (kJ mol1) [Tl(dota)]- Exp. 66 + 2 +23 + 6 59 + 2 Calcd. 73.2 +19.2 67.5 [Bi(dota)]- Exp. 40 -76 + 15 63 [Lu(dota)]- Exp. 101 +116 66 a Values obtained for the arm-rotation process with DFT calculations in aqueous solution at the B3LYP/CRENBL/6-31+G(d,p) level. The activation enthalpy (H) determined for [Tl(dota)] falls between the values reported for [Bi(dota)] and [Lu(dota)]. However, the different signals of the activation entropy obtained for the latter two complexes and the small positive S value determined for [Tl(dota)] result in relatively similar activation free energies at 298 K (G298). The 61 [Lu(dota)] complex exists in solution as a mixture of the eightcoordinate TSAP’ isomer and the nine-coordinate SAP form, and activation parameters for both the ring-inversion and arm-rotation processes could be obtained.59b Thus, the large positive activation energy obtained for this complex might be related to the expulsion of the coordinated water molecule in the transition state responsible for the ()  () interconversion. For [Tl(dota)] S takes a relatively small positive value, which is likely related to the rearrangement of the hydration shell during the interconversion process. 1.82.02.22.42.62.83.03.23.43.63.84.04.24.4 (ppm) 272.5 K 282.5 K 360.0 K 292.5 K 302.5 K 312.5 K 322.5 K 332.5 K 342.5 K 352.5 K Figure 4.1.5.3 1H-NMR spectra of 0.1 M [Tl(dota)] at varying temperatures 62 To obtain a more detailed information of the mechanism responsible for the enantiomerization process in [Tl(dota)], we performed a computational investigation of the ring inversion and arm rotation processes. Figure 4.1.5.4 Relative free energies of minima, intermediates (labeled as “I”) and transition states (labeled as “TS”) involved in the ()  () interconversion process of [Tl(dota)] calculated in aqueous solution at the B3LYP/CRENBL/6-31+G(d,p) level According to our calculations performed in aqueous solution at the B3LYP/CRENBL/6-31+G(d,p) level the inversion of the macrocyclic ring is a four-step process involving the stepwise inversion each of the 63 four five-membered chelate rings formed by the coordination of the macrocyclic moiety. In each of these steps one of the chelate rings changes its configuration from  to  (or vice versa) through a transition state in which the H-C-C-H units adopt a nearly eclipsed conformation. Similar four-step processes have been obtained previously using HF and DFT calculations for different Ln3+ complexes with cyclen-based ligands.112 Due to the symmetry properties of the [Tl(dota)] complex (C4 point group), two different routes are possible for the inversion of the second and third chelate rings (Figure 4.1.5.4). As once the first chelate is inverted, the second step may proceed via inversion of a chelate ring either in opposite (TS2a & TS3a) or adjacent (TS2b & TS3b) position at the macrocyclic ring with respect to the former. According to our calculations the lowest-energy pathway corresponds to that proceeding through TS3b, which provides an activation Gibbs free energy for the ring-inversion process of G = 60.8 kJ mol1 at 298 K. Contrary to the ring-inversion process, the arm rotation pathway is a single-step process involving the simultaneous rotation of the four pendant arms of the ligand. The structure of the TS (TS5, Figure 4.1.5.4) is quite distorted, with four different Tl-N distances in the range 2.502.75 Å and four Tl-O distances ranging between 2.30 and 2.37 Å. The activation free energy for the arm rotation process amounts to G298 = 67.5 kJ mol1, and thus the arm-rotation process likely represents the rate determining step for the ()  () interconversion in [Tl(dota)]. The H and S values calculated for the arm rotation pathway (Table 4.1.5.1) show a very good agreement with the experimental values, which provides additional support for this 64 hypothesis. In contrast, the ring inversion path provides negligible activation entropy. 4.2. Characterization of [Tl(cdo2a)]+ and its iodido mixed-ligand complex 4.2.1. Background of ligand choice Although [Tl(dota)] has proven to be quite robust, it lacks the free metal coordination site needed for binding additional anions. Logic dictates and experience has shown that ligands with fewer pendant donor sites should leave the encapsulated metal more accessible to water molecule(s) or additional small anion(s). To this end, the iodide-binding ability of various Tl(III)-complexes was investigated by 205Tl-NMR, using a number of macrocyclic (and one mesocyclic) ligands. The ligands investigated are, in descending order of the number of donor sites: do3a (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), pcta (3,6,9,15tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), aazta (2,2'-(1,4-bis(carboxymethyl)-6-methyl-1,4-diazepan-6ylazanediyl)diacetic acid), cysand trans-do2a (1,4,7,10tetraazacyclododecane-1,4-diacetic acid and 1,4,7,10tetraazacyclododecane-1,7-diacetic acid) and do1a (1,4,7,10tetraazacyclododecane-1-acetic acid). To much of our surprise only one of the ligands, cdo2a was found to bind iodide ions in its Tl(III)-complex. This fact is especially interesting when DFT calculations performed for both do2a isomers are taken into consideration: not only is [Tl(tdo2a)]+ expected to also form a ternary complex with iodide ions, it was also 65 found to be energetically more favourable than that of [Tl(cdo2a)]+. The details on why this is not the case are still unknown at this time, we speculate that steric hindrance may be quite different in the two complexes. 4.2.2. Dissociation kinetics of [Tl(cdo2a)]+ 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 200 220 240 260 280 300 320 340 wavelength, nm A Figure 4.2.2.1 Time dependence of UV-spectra attributed to the ligandexchange reaction between [Tl(cdo2a)]+ and Brin 1M HClO4: [Tl(cdo2a)Br] (bottom black, recorded at t0) is slowly converted to [Tl(Br)4] (top black, recorded at 15 hours; the absorbance value and the shape of the spectrum are in accordance with separate measurements of [TlBr4]) 66 The double competition method described earlier in case of [Tl(dota)]− was used to also determine the dissociation properties of [Tl(cdo2a)]+, with the latter showing some similarity to the former (see Figure 4.2.2.1). The initial absorbance is greater, likely as a consequence of [Tl(cdo2a)Br] forming. The largest difference is the increased dissociation rate (obtained in the same manner as for [Tl(dota)]−), reaching total Tl(III)-displacement in 1M HClO4 overnight, as less donor groups make the complex less compact and the metal center more accessible. 4.2.3. Acid-base properties of [Tl(cdo2a)]+ The parent complex can form mixed hydroxo complexes according to the following equations: [Tl(cdo2a)]+ + H2O [Tl(cdo2a)OH] + H+ (4.2.3.1) [Tl(cdo2a)OH] + H2O [Tl(cdo2a)(OH)2]– + H+ (4.2.3.2) The stability constants of [Tl(cdo2a)OH] and [Tl(cdo2a)(OH)2]– were determined via pHpotentiometry and were found to be lgKOH[Tl(cdo2a)] = - 7.37(8) and lgKOH[Tl(cdo2a)OH] = -11.10(9). With two less donor sites than in dota, this complex may possess up to two coordinated water molecules, however the significant difference between the two values indicates that the complex most likely has only one and the second coordinated OH– most likely replaces a carboxylate moiety. 67 4.2.4. Investigation of the iodido-mixed ligand complex [Tl(cdo2a)I] Formation of the mixed iodido complex can be described by the next equilibrium: [Tl(cdo2a)]+ + I– [Tl(cdo2a)I] (4.2.4.1) To determine the stability of the [Tl(cdo2a)I] mixed-ligand complex, shown in eq. 4.2.4.1, potentiometric and NMR titrations were carried out, shown in Figures 4.2.4.1 and 4.2.4.2. The effect of OH––competition was avoided by keeping the pH in a range of 3–4. Potentiometric titrations were performed on samples containing 1 mM [Tl(cdo2a)]+ at pH = 4 in 1 M NaClO4. 205Tl-NMR of [Tl(cdo2a)]+ shows a signal at δ = 2500 ppm, with a half-width of w½ = 5500 Hz, similar in chemical shift, but rather broad compared to [Tl(dota)]− (w½ = 2200 Hz). This may be attributed to lower overall rigidity and compactness. The signal of [Tl(cdo2a)I] appears at δ = 1230 ppm (more than 1200 ppm downfield). Using the same principles and methods as for [Tl(dota)]− the formation constant of lgKI[Tl(cdo2a)] = 4.1±0.1 was obtained, making this ternary complex somewhat less stable than [Tl(edta)I]2–. This is to be expected of macrocyclic complexes, as the coordinated metal ion is much less accessible than with open-chain ligands. Even so, [Tl(cdo2a)I] is relatively stable as mixed ligand complexes go. 68 -250 -200 -150 -100 -50 0 2345 -lg cI(tot) E, mV Figure 4.2.4.1 Potentiometric titration curve of [Tl(cdo2a)]+ (hollow squares) and calibration points (black triangles) using iodide-selective electrode. 1 mM [Tl(cdo2a)]+ at pH = 4 in 1 M NaClO4 69 Figure 4.2.4.2 205Tl NMR titration of 9 mM [Tl(cdo2a)]+ with 1.107 M NaI at pH = 4. I = 1 M NaClO4 4.2.5. Comparison with a rigidified open-chain complex [Tl(cdtabba)]+ Although the investigation of Tl(III)-complexes of open-chain ligands was not the primary goal of this work, it is worth comparing 76 The formation of [Al(nota)(F)]– was almost 100 % in 50 % ethanol after 15 min of heating according to the 19F-NMR spectrum (Fig. 4.3.2). The chemical shift was -48 ppm, slightly different from the –47 ppm measured in water likely due to a solvent effect. The role of ethanol could be related to the decreased basicity of the ring nitrogen donor atoms in nota,117 resulting in faster complex formation due to weaker competition between the H+ ion and Al(III) for the donor atoms of the macrocycle. Figure 4.3.2 376.5 MHz 19F-NMR spectra of samples containing Al(III), nota and F– in equimolar amounts (4 mM each) after heating in pH = 4 acetate buffer for varying times at 100 °C A detailed study of formation kinetics for metal-macrocyclic complexes in mixed solvents is in progress in our laboratory. Preliminary results show that complex formation kinetics are fairly complicated in the Al(III)–nota–H+–F– four-component system, further experiments should be performed to describe and understand the formation kinetics of the mixed ligand complex. 77 4.4. Characterization of [Tl2{B-β-SiW8O30(OH)}2]12–, a newly synthesised thallium-containing polyoxometallate Although thallium(I) salts of conventional di-, paraand metatungstates have been prepared by usual methods (Tl2O·WO3, Tl2O·2WO3, 5Tl2O·12WO3, Tl2W4O13 and Tl0.3WO3), 118 , 119 these compounds are tungsten oxides with an extended structure and to date no structurally characterized discrete Tl-containing polyanions have been reported. In this work we also present data on the synthesis and solution characterization of the novel, thallium(III)-containing 16-tungsto-2silicate [Tl2{B-β-SiW8O30(OH)}2]12-, which represents the first structurally characterized discrete thallium-containing metal-oxide. In the polyanion, two octahedrally coordinated Tl3+ ions are sandwiched between two lacunary {B-β-SiW8} Keggin-type fragments (Fig. 4.4.1.1). 4.4.1. X-ray crystal structure Single crystal X-ray analysis revealed that the compound crystallizes in a monoclinic crystal system with space group P21/m. The [Tl2{B-β-SiW8O30(OH)}2]12– architecture presents a polyanion with idealized C2h symmetry, which consists of two thallium(III) centers and two {B-β-SiW8O31} POM units. The {B-β-SiW8O31} units were formed from the [γ-SiW10O36]8– precursor by rotational isomerization and loss of tungsten. The first POM comprising a {B-β-SiW8O31} unit was reported in 2005. 120 The {M2(B-β-SiW8O31)2} structure type has been seen before.121 The two equivalent thallium(III) centers in the polyanion are both six-coordinated, and each thallium ion is coordinated to two {B-β- 78 SiW8O31} lacunary POM fragments via four terminal O atoms of the two complete tungsten-oxo triads and two terminal O atoms of two {SiO4} hetero groups. The Tl-O bond length ranges from 2.156(1) to 2.238(1) Å, and the distance between both thallium atoms is 3.338(1) Å. Bond valence sum (BVS) calculations122 confirm that the oxidation state of the two thallium centers is +3. As based on elemental analysis, the polyanion is diprotonated and BVS as well as DFT (vide infra) suggest that they are located on the two μ3-O atoms. Figure 4.4.1.1 Polyhedral representation of [Tl2{B-βSiW8O30(OH)}2]12– (1). Color legend: WO6 (dark red) octahedra, SiO4 (dark grey) tetrahedra, Tl (light blue), O (light red). The most basic types of oxygens are labeled as OA, OB and OC. The tungsten atoms WA and WB have different 203/205Tl–183W spin-spin coupling constants Preliminary DFT calculations were performed in order to evaluate the most probable protonation sites and proton distribution in aqueous solution. The structure was optimized initially for the non-protonated anion [Tl2{B-β-SiW8O31)}2]14– and the most characteristic X-ray bond 79 distances were rather well reproduced: Tl-O(Si) 2.28 Å, W-O(Si) 2.25 - 2.43 Å, W-O(Tl) ca 1.81 Å, and Tl···Tl 3.37 Å. 4.4.2. Solution structure study [Tl2{B-β-SiW8O30(OH)}2]12– is sufficiently soluble in water to record 205Tl and 203Tl NMR spectra of reasonable quality (Figure 4.4.2.1). Both isotopes have a spin of 1/2, and a natural abundance of 70.5 % and 29.5%, respectively. At first sight, both spectra appear as pseudo-triplets, attributed to the spin-spin coupling between two sterically identical Tlatoms. The central peaks are assigned to polyanions with homonuclear 205Tl-205Tl or 203Tl-203Tl coupling, whereas the satellite peaks belong to heteronuclear 205Tl-203Tl coupled polyanions, respectively. The peak intensities of the pseudo-triplets agree very well with the expected ones from the isotope ratios, 29.5/2 : 70.5 : 29.5/2 (205Tl NMR), and 70.5/2 : 29.5 : 70.5/2 (203Tl NMR), see SI for details. This finding is in full agreement with the solid-state structure having two Tl-atoms in identical positions, and it proves unequivocally that the dimeric structure is preserved in solution. The chemical shift difference between the satellite peaks represents the coupling constant, 2J(205Tl-203Tl) = 2670 Hz. Interestingly, a closer look at the spectra indicates further fine structure of the recorded peaks caused by spin-spin coupling with 183W atoms (14.3%). The two different values for 2J(203Tl-183W) are ca. 470 and 350 Hz, respectively, and the corresponding values for 2J(205Tl-183W) are ca 1% larger (see Figure 4.4.2.1 caption for details). These values can be rationalized by coupling to two structurally inequivalent types of tungsten being two bonds away from the thallium centers. These couplings may 80 actually be averaged effects of two types of 183W centers (WA, WB) with similar chemical environments. The Tl···W distances are 3.64 and 3.65 Å for WA, and 3.72 and 3.73 Å for WB, respectively. Figure 4.4.2.1 Experimental (black) and theoretically simulated (red) 144.26 MHz 205Tl (top) and 142.86 MHz 203Tl NMR (bottom) spectra of [Tl2{B-β-SiW8O30(OH)}2]12–, ~6 mM in 0.04 M acetic acid/sodium acetate buffer, pH = 4.1. Coupling constants shown: a) 2J(205Tl-183WA) ca. 475 Hz, b) 2J(205Tl-183WB) ca. 354 Hz, c) 2J(203Tl-183WA) ca. 470 Hz, d) 2J(203Tl-183WB) ca. 350 Hz and e) 2J(205Tl-203Tl) = 2J(203Tl-205Tl) ca. 2700 Hz (same value in both spectra) 81 However, the relatively broad spectral lines prohibit such a detailed investigation. The 1H couplings do not play a role because of fast exchange, and the effects of 29Si (I = 1/2, 4.7%) and 17O (I = 5/2, 0.037 %) are also not detectable. 4.4.2.1. Simulation of Tl NMR spectra We have also simulated the Tl NMR spectra considering the symmetry, the relative positions of the Tl and W atoms, the natural abundance of the NMR-active nuclei and the spin-spin coupling constants measured experimentally. The experimentally obtained NMR spectra are superpositions of several spectra with different combinations of NMRactive nuclei. The NMR model used for simulation is based on the solidstate structure of the polyanion. Three (I = 1/2) isotopes, 203Tl, 205Tl and 183W (natural abundances 0.295, 0.705, and 0.143, respectively), and geminal spin-spin couplings are taken into consideration. The two Tl atoms in the polyanion are sterically identical with C2h symmetry. One Tl may be coupled with the other Tl and at most four W nuclei (of two different types: two WA and two WB). The three identified independent coupling constant values are 2J(203Tl, 205Tl) = 2670 Hz, 2J(203Tl, 183WA) = 470 Hz, and 2J(203Tl, 183WB) = 350 Hz. The four other coupling constants (2J(205Tl-183WA), 2J(205Tl-183WB), 2J(203Tl-203Tl) and 2J(205Tl-205Tl)) used differ only by 1%, because the magnetogyric ratio, which they are proportionate to, is 1% higher for 205Tl than for 203Tl. If the natural abundance of the observed isotope equals p (p = 0.295 or p = 0.705), then the ratio of polyanions containing 2, 1 and 0 observed Tl-isotopes is defined by the binomial distribution and their NMR signal intensity ratio can be calculated by multiplying with said numbers: 2·p2 : 1·2·p·(1-p) : 82 0·(1-p)2 = p : (1-p) : 0. The polyanions with two observed Tl isotopes or two different Tl isotopes produce different NMR signals, which are separated because of 2J(Tl-Tl) >> 2J(Tl-183W). In the multiplets assigned to heteronuclear Tl-Tl coupling (satellite signals) all couplings are first-order and the Tl-Tl coupling produces a symmetric doublet. The 183W-couplings are more complicated, owing to the two different coupling constants. For each satellite, coupling of 1, 2, 3, or 4 183W nuclei results in 4, 9, 12, or 9 peaks, respectively. If p = 0.143, then the intensity of the satellite is shared among polyanions containing 0, 1, 2, 3, and 4 183W couplings with probabilities of (1-p)4, 4·p·(1-p)3, 6·p2·(1-p)2, 4·p3·(1-p), p4 (0.54, 0.36, 0.09, 0.01 and 0.0004) respectively, according to the binomial distribution (see Table 4.4.2.1.1). The central peak will rise to 58.5 % intensity, caused by splitting, the following four observable signals will be 9.2% each and the intensity left for all other signals is <5%. The coupling constants can be obtained from the satellite peaks. In multiplets assigned to homonuclear Tl-Tl coupling (central signals) without 183W coupling, the two Tl nuclei are magnetically equivalent (A2 spin system) providing a singlet signal with a chemical shift δ = 2206 ppm. The 183W coupling causes magnetic non-equivalence of the two Tl centers, so the simple first-order coupling cannot be used any further. Formulae used in the case of ABX (more precisely AA’X in our case) spin systems are known.123 Tungsten is only coupled to one of the two thalliums (A-A’-X), resulting in J(A’,X) = 0 for the other one and resulting in 4 doublets. The distance between two doublets is greater than 5400 Hz and their intensity is at most 0.4% of all others, making them unobservable (lost in the noise). The distance of the other two doublets is 83 half the coupling constant (ca. 240 or 180 Hz) and they are split by only ca. 11 Hz or 6 Hz, meaning that they are not sufficiently separated to be observable. Table 4.4.2.1.1 Breakdown of the spin systems and their contribution to the intensity pattern observed in the Tl NMR spectra of [Tl2{B-βSiW8O30(OH)}2]12– Central peaks (Homonuclear Tl-Tl coupling) No. of coupled 183W nuclei Satellite peaks (Heteronuclear Tl-Tl coupling) No. of spin systems Intensity contribution No. of spin systems Intensity contribution 1 29.15% 0 1 54.0% 2 38.85% 1 2 36.0% 6 22.65% 2 3 9.0% 8 7.55% 3 2 1.0% 11 1.57% 4 1 0.04% 8 0.21% 5 6 0.017% 6 6 0.00083% 7 1 0.000017% 8 Four similar doublets appear when considering both coupling constants. The coupling of two 183W centers requires numerical solution of six different spin systems (34 observable peaks). Fortunately, simulation with first-order couplings and constants of 2J(Tl-183WA)/2 and 2J(Tl-183WB)/2 produces an almost identical spectrum at the used line-width of 60 Hz; i.e. this simplification could be used for polyanions with 3, 4, 5, 6, 7, 8 183W 84 isotopes, having almost negligible contributions. The intensity of the central multiplet is shared between polyanions containing 0, 1, 2, 3, …, 8 183W couplings with probabilities of (1-p)8, 8·p·(1-p)7, …, p8 (0.292, 0.389, 0.227, 0.076, 0.016, …, 1.7×10-7), respectively, according to the binomial distribution (see Table 4.4.2.1.1). Summing up the intensities of close signals raises that of the central signal to 41.1 %, the next 4 signals will be 11.2 % each (however, their separation is only 30 Hz per pair), and finally “shoulders” with 6.1 % intensity each appear on both sides. In order to visualize the complexity of the numerous spin systems, we have simulated both the 205Tl and 203Tl NMR spectra using Lorentzians with 5 Hz linewidth and plotted them together with the experimental spectra (Figure 4.4.2.1.1). The similarity in shape and positions of peak maxima is obvious. 85 Figure 4.4.2.1.1 Experimental (black) and theoretical (simulated with 5 Hz line-width, red) 144.28 MHz 205Tl and 142.88 MHz 203Tl spectra of [Tl2{B-β-SiW8O30(OH)}2]12-. Calculations were performed with a homemade MATLAB program and a few spin systems were simulated with WINDNMR The chemical shift value of ca. 2206 ppm (the position of the centralpeaks, referenced to infinitely diluted TlClO4 as 0 ppm) is consistent with a +3 oxidation state for the thallium atoms being sixcoordinated to O atoms in an octahedral geometry in water. 124 ,27 92 The MIC values presented are promising, as the polyanion effects all tested organisms at similar –and in most cases, lower– Tl-concentrations than inorganic thallium salts. Considering the solution data obtained the inhibitory effect is unlikely to stem from the release of thallium from the POM, as the concentrations used in the biological study are several orders higher (µM) than those at which the POM would noticeably dissociate (nM). 93 4.5. Characterization of another novel Tl(III)-containing POM, [Tl2{P2W15O57}2]22– Figure 4.5.1 Polyhedral representation of [Tl2{P2W15O57}2]22– (1). Color legend: WO6 (red) octahedra, PO4 (blue) tetrahedra, Tl (green), O (light red), Na (brown) A similar compound to the one described above, [Tl2{P2W15O57}2]22– was also synthesized in Bremen and is very similar to [Tl2{B-β-SiW8O30(OH)}2]12 with a few key differences. This polyanion has a different symmetry, being based on a lacunary WellsDawson structure and contains phosphate as a heterogroup instead of 94 silicate. Two thalliums are sandwiched between two POM fragments, similarly to [Tl2{B-β-SiW8O30(OH)}2]12. As 31P is also a I = ½ nucleus but with 100% natural abundance, further peak splitting is to be expected and 31P NMR becomes an additional tool to investigate it with. The 31P NMR spectrum in Fig. 4.5.2 was provided by our partners in Bremen. Figure 4.5.2 162.14 MHz 31P NMR spectrum of 3.7 mM [Tl2{P2W15O57}2]22– in 0.5 M phosphate buffer pH = 5.8. Both 205 and 203Tl NMR spectra were recorded from a sample made from 49 mg of the compound in 2.5 ml of water. The 31P NMR shows a triplet 95 and a singlet peak, which can be assigned to the two phosphorous atoms that are coupled to both Tl-nuclei and the two that are isolated, respectively. The Tl NMR spectra however, show one major and one minor signal which do not synergize with the pattern seen in the 31P NMR. Making the assumption that the major signal may be most likely attributed to the title ion, we have focused on interpreting it first. The following coupling constants were obtained or estimated: 2J(P-Tl) ≈ 225 Hz (from the 31P spectrum, 2J(205Tl-203Tl) ≈ 777 Hz, 2J(Tl-183W) > 500 Hz. The spectra clearly exhibit different peak structures, indicating that the examined molecule does indeed contain two thallium nuclei within coupling distance, as in [Tl2{B-β-SiW8O30(OH)}2]12–. In this case however, the satellite and central signals are much less separated and there are also two coupling 31P nuclei introducing additional splitting and overlap. Even so, the same principles can be applied in this case as well. The major signals in both 203 and 205Tl NMR spectra were deconvoluted by treating each of them as a sum of constituent spectra belonging to molecules with only homoor heteronuclear Tl-Tl coupling (somewhat akin to the evaluation of UV-vis spectra). The experimentally obtained spectra can be reconstructed per-point by adding these constituent spectra together in different proportions (determined by natural isotope abundances), as seen in Fig. 4.5.4. The polyanion clearly retains its structure in solution, however we currently have no data on what the minor signal might be attributed to. 96 Figure 4.5.3 144.28 MHz 205Tl NMR (above) and 142.86 MHz 203Tl NMR (below) spectra of [Tl2{P2W15O57}2]22– (below) 97 Figure 4.5.4 Deconvolution of the [Tl2{P2W15O57}2]22– Tl NMR spectra: 205Tl (above, black) and 203Tl (red, below). Constituent spectrum 98 intensities are also shown in each (homonuclear: blue and heteronuclear: green) 99 5. Summary This thesis deals with Tl(III)-complexes of two, fundamentally different multidentate ligand types,: organic polyaminopolycarboxylates and inorganic heteropolytungstates, which even so share some similarities. We have studied solution equilibrium and kinetic properties, as well as structural traits both in solid and solution phase, of various Tl(III)- complexes. Structural properties of [Tl(dota)] have been explored both in solid phase and solution. In solid state, the Tl3+ ion is directly coordinated to the eight donor atoms of the ligand, with the metal coordination environment being best described as twisted square antiprismatic (TSAP); the coordination of the ligand to the metal ion introduces two sources of stereoisomerism, one associated to the conformation of the cyclen moiety [() or ()], and another related to the layout of the four acetate pendant arms [represented as  or ]. Inspection of the structure shows that crystals contain the ()/() enantiomeric pair, the two enantiomers being centro-symmetrically related in accordance with the centro-symmetric character of the space group P-1. The “soft” nature of Tl3+ (and Bi3+) according to the Pearson classification provokes a strengthening of the coordination bonds with the softer N donor atoms, which results in a deeper penetration of the metal ion into the macrocyclic cavity and the preclusion coordination of further water molecules or small ions to the metal center. 100 The acid–base properties and affinities towards mixed–complex formation were investigated for [Tl(dota)]− and [Tl(cdo2a)]+. The coordinative saturation around the metal center and overall compactness in [Tl(dota)]− makes further coordination of small anions –even those with high affinity towards Tl(III)– unfavourable. [Tl(cdo2a)]+ was found to form a relatively stable mixed–complex with iodide ions. The complexes are highly resistant towards dissociation via proton– or OH–– assisted pathways. [Tl(dota)]− does not deprotonate in the pH–range 4– 11, as there is no room for a Tl–coordinated water molecule in the complex, however a protonation constant of pKH[Tl(dota)] = 1.4±0.1 was be obtained from 205Tl-NMR. This process most likely involves the protonation of one of the carboxylate arms. It is likely that [Tl(dota)]− may be stored on any measurable pH indefinitely. Conversely, [Tl(cdo2a)]+ does have coordinated water and can be deprotonated twice (lgKOHTl(cdo2a) = –7.37±0.01, lgKOHTl(cdo2aOH) = –11.10±0.01). Protonation at low pH has not been measured, although the complex stays intact in the pH–range 0–12 for months. [Tl(dota)]− does not form mixed–complexes generally, due to the metal being virtually completely wrapped by the ligand donor groups. Only the formation of a faint mixed [Tl(dota)(CN)]2– complex could be detected using 205Tl-NMR, with Kmix = 6.0 ± 0.8. This is several orders of magnitude lower than other cyanido–mixed Tl(III)–complexes (in case of [Tl(edta)]– lgKmix = 8.7) and even the protonation of cyanide is enough for it to instantly dissociate. [Tl(cdo2a)]+ readily forms halido–mixed ligand complexes, such as [Tl(cdo2a)I] as evidenced by potentiometric titrations and Tl NMR. A formation constant of lgKI[Tl(cdo2a)] = 4.1±0.1 is obtained from both potentiometry with an iodide-selective electrode and 101 205Tl NMR titrations in the pH–range 3–4 (avoiding the interference of OH–). Dissociation kinetics of [Tl(cdo2a)]+ and [Tl(dota)]− were investigated with UV-spectrophotometry. Both complexes were found to be highly stable and inert against dissociation, requiring large excesses of competing agents –both for the metal and the ligand– for the dislocation of Tl(III) to occur in reasonable time spans. Several attempts were made to determine the stability of both [Tl(cdo2a)]+ and [Tl(dota)]− using the double competition method previously described for [Tl(edta)]–, using large (in some cases, several thousand–fold) excesses of both Br– and H+ in batch samples, followed via UV–spectrophotometry. True equilibriation could not however be reached in case of either complex, as some unknown side–reaction takes place which interferes with the evaluation of UV–spectra from then on. Insight into the dissociation of [Tl(dota)]− was however obtained, showing quadratic dependence of kobs on acidity, with no detectable spontaneous dissociation. This kind of rate law is in accordance with the related literature of dota-complexes, i.e. the dissociation is a dominantly proton-assisted process. Using the kobs = k1[H+] + k2[H+]2 rate law, the half–life of the complex at different pH values can be calculated. Half-life of [Tl(dota)] is 32 h in 1 M HClO4 and approximated to 5▪109 h (more than half millon years) at pH = 7.4. The latter value indicates that the dissociation of [Tl(dota)]− at the physiological pH of blood is negligible. [Tl(cdo2a)]+ behaves similarly, with faster dissociation and lower acid concentrations needed to initiate the process. 108 hatására játszódott le, akkor is igen lassan. Nagyszámú kísérletet végeztünk a [Tl(cdo2a)]+ és [Tl(dota)]− stabilitási állandóinak meghatározására, a [Tl(edta)]––hoz korábban sikeresen használt kettős kompetíciós módszerrel, nagy (esetenként többezerszeres) feleslegben használt Br– és H+ ionokkal. Különmintás módszert használva, a változásokat UV–spektrofotometriával követtük. Valódi egyensúlyt nem értünk el, mivel hosszabb idő elteltével valamilyen ismeretlen mellékreakció is elindul és kiértékelhetetlenné teszi a további adatokat. Sikerült azonban belátást nyerni a [Tl(dota)]− disszociációs folyamatába, a kezdeti sebességek módszerével. Az illesztett görbe azt mutatja, hogy kobs négyzetesen függ a savkoncentrációtól, spontán disszociáció pedig nem észlelhető. Ez a fajta sebességi egyenlet egyezik a dota-komplexek ide vonatkozó irodalmában leírtakkal, a bomlás főként proton-asszisztált folyamat, A kobs = k1[H+] + k2[H+]2 egyenletet felhasználva kiszámítható a komplex felezési ideje különböző pH-kon. A [Tl(dota)] esetében ez 32 óra 1 M HClO4–ban és megközelítőleg 5▪109 óra (több mint félmillió év) pH = 7.4–en. Ez utóbbi érték azt mutatja, hogy a vér fiziológiás pH-ján a komplex disszociációja elhangyagolható. A [Tl(cdo2a)]+ hasonlóan viselkedik, de gyorsabban disszociál (4 óra 1 M HClO4–ban és 786 óra pH = 7.4–en) és a folyamat alacsonyabb savkoncentrációknál is megkezdődik. A [Tl(dota)]− oldatbeli izomer-interkonverziójának dinamikáját is vizsgáltuk. A komplex oldatban két TSAP enantiomer (() és ()) egyensúlyi keverékeként van jelen. A különböző hőmérsékleteken felvett 13C-NMR spektrumokban megfigyelt jelalakváltozást az oldatban jelenlevő, egyenlő populációjú két izomer közti 109 egyszerű cserefolyamathoz rendeltük. A folyamat magában foglalja a makrociklus inverzióját [()  ()] és a négy acetát kar rotációját [  ]. Szerencsénkre, a teljes lassú–gyors csere átmenet végigkövethető volt szokványos hőmérsékleteken és kvantitatív jelalakanalízissel minden hőmérsékletre kiszámolható a kétlépéses folyamat cseresebessége kexch, majd ezekből a folyamat aktiválási paraméterei. Az így kapott értékek jó egyezést mutatnak a DFT számolásokból származóakkal. A [Tl(dota)]–hoz szerkezetében és robusztusságában némileg hasonló [Al(nota)] komplex részletes vizsgálatát elvégeztük. (Ilyen Alkomplexeket használnak anionhordozóként 18F PET vizsgálatokhoz, amelyekben a „kemény” Al(III) köti meg a „kemény” fluoridot. Ez szolgált számunkra alapul „lágy-lágy” kölcsönhatáson alapuló Tl(III)- jodid vegyeskomplexek tervezésére.) Az irodalomban leírtakkal ellentétben, vegyesligandumú [Al(nota)(F)]– képződése nem figyelhető meg sem potenciometriával, sem 19F NMR–el [Al(nota)] és F– közvetlen reakciójában. A terner komplex Al(III)-t, F–-t és nota-t egyenlő koncentrációban tartalmazó oldatokból, melegítés hatására képződik észlelhető mennyiségben, de egyensúlyi adatok nem születtek. Ugyanakkor a vegyeskomplex szinte kvantitatíve képződik 15 perc melegítés után, ha oldószerként 50% etanolt választunk. Ez valószínűleg egy többlépéses kompetíciós reakció a különböző Al(III)-fluorido komplexek és a nota közt, melyben a [Al(nota)(F)]– egy intermedier, mivel hosszabb melegítés minden esetben csökkenti a vegyeskomplex arányát és [Al(nota)] képződik. 110 Megvizsgáltuk két tallium-tartalmú POM oldatbeli szerkezetét, a szilárd (NH4)5K7[Tl2{B-β-SiW8O30(OH)}2]·19H2O–ban a [Tl2{B-βSiW8O30(OH)}2]12szerkezet idealizált C2h szimmetriájú polianion, mely két tallium(III) magból és két {B-β-SiW8O31} POM egységből építhető fel. A {B-β-SiW8O31} egységek a [γ-SiW10O36]8– prekurzorból képződnek rotációs izomerizáció és wolfram vesztés során. A két tallium(III) hatszorosan koordinált és mindkét tallium ion két {B-β-SiW8O31} hiányos POM fragmenst köt össze, a két egész wolfram-oxo triád 4 terminális oxigénjével és két {SiO4} heterocsoport két terminális oxigénjével kapcsolódik. Ez a szerkezet változatlanul megmarad oldatfázisban is és két skalárisan csatoló tallium magot tartalmaz, amit 205Tl és 203Tl NMR spektrumok egyértelműen bizonyítanak. Első ránézésre mindkét spektrum pszeudo–tripletnek tűnik, amit a két sztérikusan azonos, spin-spin csatolásban lévő Tl-atomhoz rendelhetünk. A jelek további finom szerkezete is megfigyelhető a 183W atomokkal (14.3%) történő csatolások miatt. A 2J(203Tl-183W) két különböző értéke kb. 470 és 350 Hz és az ide tartozó 2J(205Tl-183W) értékek ~1%–kal nagyobbak. Ezeket az értékeket kétféle, nem-ekvivalens wolfram atomokkal való csatolással lehet magyarázni. A [Tl2{B-β-SiW8O30(OH)}2]12szimmetriáját, a Tl és W magok relatív pozícióit, az NMR-aktív magok természetes előfordulásait és a mért csatolási állandókat figyelembe véve szimulált spektrumokat is készítettünk. Valójában a kísérletileg kapott spektrumok nagy számú rész-spektrum szuperpozíciói, melyekben különböző számban és helyen szerepelnek NMR-aktív magok. A szimulált modellünkben csak a Tl-OTl és Tl-O-183W csatolásokat vettük figyelembe, így 54 különböző 111 lehetséges spinrendszert kaptunk. A középponti és szatelit csúcsok közti jól látható alakkülönbség annak tudható be, hogy a 183W magok homonukleárisan csatolt (A2 spinrendszer) Tl-atomokkal csatolnak, megzavarva a két sztérikusan azonos 205Tl vagy 203Tl mag mágneses ekvivalenciáját, ezzel AA’X spinrendszert eredményezve. Ilyen esetben a Tl-W felhasadás pontosan feleakkora, mint a szatelit jelekben. Ez a jelenség megfigyelhető a [Tl2{P2W15O57}2]22––ban is, viszont ebben az esetben kisebb a távolság a középponti és szatelit jelek közt és a két, csatolási távolságban levő 31P mag (100% természetes előfordulással) további felhasadást eredményez minden tallium jelben. Ez a vegyület is jól láthatóan megőrzi szerkezetét oldatfázisban is, és a kísérletileg kapott 203Tl és 205Tl NMR jelek jól felépíthetőek megfelelő arányú tisztán centrális és szatellit jelek intenzitásainak öszegeként. A Tl-NMR spektrumokban található egy további, kisebb jelcsoport, ami szintén láthatóan két Tl(III) magot tartalmaz, de a jelalakja és a kémiai eltolódása is más. A [Tl2{B-β-SiW8O30(OH)}2]12NMR–titrálása, melyben kompetíciós ionként acetátot használtunk, a vegyület stabilitására enged következtetni. Nagy acetát felesleg mellett, több nap alatt sem történt kimutatható reakció. A vegyületet két tallium és két {B-β-SiW8O31} egység M2L2 komplexeként kezelve, ismerve a Tl(Ac)4– komplex stabilitását, becsülhető egy lgK > 40–es minimum stabilitási állandó. (Érdemes azonban megjegyezni, hogy a poliwolframátok reakciói gyakran extrém lassúak, tehat nem zárható ki „metastabilis”, nem egyensúlyi viszonyok kialakulása sem). A látszólagos stabilitási állandó alapján extrapolálható, hogy hígulás miatti disszociáció a vegyületben 112 csak szub-nanomoláris koncentrációknál válik jelentőssé. Ezek mellett megemlítendő, hogy a [Tl2{B-β-SiW8O30(OH)}2]12erősen savas közegben állás közben poliwolframátok keverékévé bomlik, melyek 205Tl NMR vizsgálataink szerint már csak egy-egy Tl(III)-t tartalmaznak. Ehhez hónapokat kell várni és a mintákban disszociált talliumot – akár Tl(III) akva ionként, akár Tl2O3 oxidként, vagy acetáto-komplexként– továbbra sem lehet kimutatni. 113 7. References 1 A. G. Lee, ‘The Chemistry of Thallium’, Elsevier, Amsterdam, NY, 1971. 2 A. J. 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Tamás Fodor, István Bányai, Attila Bényei, Carlos Platas-Iglesias, Mihály Purgel, Gábor Horváth, László Zékány, Gyula Tircsó and Imre Tóth: [TlIII(dota)]: An extraordinary robust macrocyclic complex Inorg. Chem., 2015, 54 (11), pp 5426–5437. IF: 4.762 (2014) 1. Edit Farkas, Tamás Fodor, Ferenc K. Kálmán*, Gyula Tircsó and Imre Tóth: Equilibrium and Dissociation Kinetics of [Al(1,4,7-triazacyclononane-1,4,7triacetate)] ([Al(nota)]) Complex, Reaction Kinetics, Mechanisms and Catalysis, 2015, 116(1), 19-33. IF: 0.983 (2013) 8.2. Presentations related to the dissertation 5. Fodor Tamás, Ayass W. W., Zékány László, Bodor Andrea, Kortz U., Tóth Imre: Dimer vagy monomer? 203/205Tl NMR homoés heteronukleáris spin-spin csatolások heteropolimetallátok oldataiban 50. Komplexkémiai Kollokvium, Balatonvilágos, 2016. május 30-június 1, 4. T. Fodor, W. W. Ayass, L. Zékány, A. Bodor, U. Kortz and I. Tóth: Homonuclear and heteronuclear Tl-Tl NMR spin-spin coupling as structural tool in solution Magyar NMR Munkabizottság 2016. évi ülése, MTA DAB Székház, Debrecen, 2016. május 20-21. 3. Fodor Tamás, Rozinka Felícia, Carlos Platas-Iglesias, Zékány László, Bényei Attila, Purgel Mihály, Kálmán Ferenc Krisztián, Tircsó Gyula, Tóth Imre: Vegyesligandumú Tl(III)-komplexek egyensúlyi és kinetikai vizsgálata, 20. Nemzetközi Vegyészkonferencia, 2014, November 6-9, Kolozsvár, Románia. 2. Fodor Tamás, Garda Zoltán, Rozinka Felícia, Kálmán Ferenc Krisztián, Kovács Zoltán, Tircsó Gyula és Tóth Imre: Vegyesligandumú tallium(III)-komplexek egyensúlyi és kinetikai vizsgálata, XLVIII Komplexkémiai Kollokvium, 2014, Május 2830, Siófok, Magyarország. 1. Tamás Fodor, Carlos Platas-Iglesias, Mihály Purgel, László Zékány, Attila Bényei, Imre Tóth: TlDOTA: an extraordinarily stable complex XLVI. Komplexkémiai Kollokvium, 2012, Május 21-23, Mátrafüred, Magyarország 8.3. Posters related to the dissertation 5. Tamás Fodor, Zoltán Garda, Felícia Rozinka, Gyula Tircsó, Imre Tóth Ternary complexes as anion binders: a new approach to radiolabeling Medicinal flavor of metal complexes: diagnostic and therapeutic applications, 2015. december 7-9., Orleans; Franciaország 4. Edit Farkas, Tamás Fodor, Ferenc K. Kálmán, Gyula Tircsó, Imre Tóth Equilibrium and Dissociation Kinetics of [Al(nota)] Complex Medicinal flavor of metal complexes: diagnostic and therapeutic applications, 2015. december 7-9., Orleans; Franciaország 3. Edit Farkas, Tamás Fodor, Ferenc K. Kálmán, Gyula Tircsó and Imre Tóth Equilibrium and Dissociation Kinetics of [Al(nota)] Complex COST Action TD1004, 2015. szeptember 10-11., Belgrád, Szerbia 2. Fodor Tamás, Farkas Edit Carlos Platas Iglesias, Zékány László, Purgel Mihály, Bényei Attila, Kálmán Ferenc Krisztián, Tircsó Gyula, Tóth Imre: Vegyesligandumú fémkomplexek, mint lehetséges izotóphordozók, 19. Nemzetközi Vegyészkonferencia, 2013, November 21-24, Nagybánya, Románia. 1. Tamás Fodor, Edit Farkas, Gyula Tircsó, Carlos Platas Iglesias, Mihály Purgel, László Zékány, Attila Bényei, Imre Tóth: Mixed ligand metal-complexes modeling anion binding: the hard aluminum(III) and the soft thallium(III) 11th International Symposium on the Synthesis and Applications of Isotopes and Isotopically Labelled Compounds, September 9-13, 2012, Heidelberg/Freiburg, Germany 8.4. Paper not involved in the dissertation 1. Enikő Molnár, Nathalie Camus, Véronique Patinec, Gabriele A. Rolla, Mauro Botta, Gyula Tircsó*, Ferenc K. Kálmán, Tamás Fodor, Raphaël Tripier* and Carlos PlatasIglesias*: Picolinate-Containing Macrocyclic Mn2+ Complexes as Potential MRI Contrast Agents Inorg. Chem. 2014, 53, 5136−5149 IF: 4.762 (2013) 8.5. Presentations not related to the dissertation 3. Molnár Enikő, Nathalie Camus, Véronique Patinec, Gabriele A. Rolla, Mauro Botta, Kálmán Ferenc Krisztián, Fodor Tamás, Raphaël Tripier, Carlos Platas-Iglesias, és Tircsó Gyula: Pikolinátcsoportot tartalmazó makrociklusos ligandumok Mn(II)- komplexei: egyensúly és kinetika, XXXXVIII Komplexkémiai Kollokvium, 2014, Május 28-30, Siófok, Magyarország. 2. Tircsó Gyula, Garda Zoltán, Molnár Enikő, Fodor Tamás, Kálmán Ferenc, Tei Lorenzo, Kovács Zoltán, Tóth Imre: Mn2+-komplexek: az MRI kontrasztanyag kutatás jövője vagy zsákutcája? 19. Nemzetközi Vegyészkonferencia, 2013, November 21-24, Nagybánya, Románia. 1. Garda Zoltán, Kálmán Ferenc Krisztián, Botár Richárd, Molnár Enikő, Fodor Tamás, Kovács Zoltán, Tóth Imre, Tircsó Gyula: 7-, 8-, 10-, és 12-tagú (makro) ciklusos ligandumok Mn2+-komplexeinek egyensúlyi és bomláskinetikai jellemzése XLVII. Komplexkémiai Kollokvium, 2013, Május 29-31, Mátraháza, Magyarország 8.6. Posters not related to the dissertation 2. Zoltán Garda, Enikő Molnár, Richárd Botár, Tamás Fodor, Ferenc K. Kálmán, Zoltán Kovács, Imre Tóth, Gyula Tircsó: Tuning of the thermodynamic and kinetic properties of Mn2+ complexes formed with cyclododecane derivatives: the effect of the nature of donor atoms 16. International Conference on BioInorganic Chemistry (ICBIC-16), 22-26 July, 2013, Grenoble, France. 1. Zoltán Garda, Enikő Molnár, Richárd Botár, Tamás Fodor, Ferenc K. Kálmán, Zoltán Kovács, Imre Tóth, Gyula Tircsó: Tuning of the thermodynamic and kinetic properties of Mn2+ complexes formed with cyclododecane derivatives: the effect of the nature of donor atoms Debrecen Colloquium on Inorganic Reaction Mechanisms, 11-15 June 2013, Debrecen, Hungary. 8.7. Patent claims not directly related to the dissertation 4. Botár R., Garda Z., Fodor T., Kálmán F., K., Nagy V., Tircsó Gy., Tóth I., Új ciklononán alapú vegyületek és alkalmazásuk Mn(II)-alapú MRI kontrasztanyagok ligandumaiként Magyar szabadalom, P1500563, Benyújtva: 2015. november 30. 3. Botár R., Garda Z., Fodor T., Kálmán F., K., Nagy V., Tircsó Gy., Tóth I., Új 3,6,9,15-t tetraaza-bicklo[9.3.1]pentadeka-1(14),11(15),12-trién alapú vegyületek és alkalmazásuk Mn(II)-alapú MRI kontrasztanyagok ligandumaiként, Magyar szabadalom, P1500564, Benyújtva: 2015. november 30. 2. Botár R., Garda Z., Fodor T., Kálmán F., K., Nagy V., Tircsó Gy., Tóth I., Új 2,11diaza[3.3](2,6)-piridinofán alapú vegyületek és alkalmazásuk Mn(II)-alapú MRI kontrasztanyagok ligandumaiként, Magyar szabadalom, P1500565, Benyújtva: 2015. november 30. 1. Botár R., Garda Z., Fodor T., Kálmán F., K., Nagy V., Tircsó Gy., Tóth I., Új 6-oxa3,9,15-triaza-biciklo[9.3.1]pentadeka-1(14),11(15),12-trién alapú vegyületek és alkalmazásuk Mn(II)-alapú MRI kontrasztanyagok ligandumaiként, Magyar szabadalom, P1500566, Benyújtva: 2015. november 30. 9. Acknowledgement I would like to express my gratitude to Prof. Imre Tóth for supervising me all these years, always showing me new ways to tackle obstacles and for all the help he has given me. I am grateful to Dr. Gyula Tircsó for deepening my understanding of practical synthetic chemistry and insight into finer aspects of potentiometry and relaxometry. Köszönöm Zékány Lászlónak a bonyolultabb számításokban, szimulációkban nyújtott elengedhetetlen segítségét, valamint történelmi és világpolitikai ismereteim kiterjesztését. I would like to thank Dr. István Bányai for getting me acquainted with some lesser-known inner workings of NMR and for his help with measurements. I would like to thank Dr. Mihály Purgel for his help with in silico calculations and interpretation thereof. I am grateful to Dr. Attila Bényei for his help in solving crystal structures and his patience when waiting for said crystals. Köszönöm Rózsa Bélának a munkában, különösképp a talliumelektrolízísben nyújtott segítségét. I thank Prof. Ernő Brücher for constantly providing new wisdom and knowledge. I thank my current and previous colleagues and students at the Dept. of Inorganic and Analytical Chemistry, University of Debrecen for their help and for providing a friendly, fun atmosphere. Végül szeretném megköszönni családomnak, hogy mindvégig támogattak és megteremtették a munkához szükséges atomszférát. I am grateful to the hungarian Science Research Fund (OTKA, projects K-84291 & K-109029) and COST action TD1004 for financial support.