Metal Complexes Containing Natural and Artificial Radioactive Elements and Their Applications

Recent advances (during the 2007–2014 period) in the coordination and organometallic chemistry of compounds containing natural and artificially prepared radionuclides (actinides and technetium), are reviewed. Radioactive isotopes of naturally stable elements are not included for discussion in this work. Actinide and technetium complexes with O-, N-, N,O, N,S-, P-containing ligands, as well π-organometallics are discussed from the view point of their synthesis, properties, and main applications. On the basis of their properties, several mono-, bi-, tri-, tetra- or polydentate ligands have been designed for specific recognition of some particular radionuclides, and can be used in the processes of nuclear waste remediation, i.e., recycling of nuclear fuel and the separation of actinides and fission products from waste solutions or for analytical determination of actinides in solutions; actinide metal complexes are also usefulas catalysts forcoupling gaseous carbon monoxide, as well as antimicrobial and anti-fungi agents due to their biological activity. Radioactive labeling based on the short-lived metastable nuclide technetium-99m (99mTc) for biomedical use as heart, lung, kidney, bone, brain, liver or cancer imaging agents is also discussed. Finally, the promising applications of technetium labeling of nanomaterials, with potential applications as drug transport and delivery vehicles, radiotherapeutic agents or radiotracers for monitoring metabolic pathways, are also described.

analog of Hf. In contrast to lanthanides, the actinides display a wide collection of oxidation states. As An 3+ ions they are analogs of the related Ln 3+ ions, but as An 4+ they resemble both Hf(IV) and Ce(IV) compounds. Actinides form various An m+ (m = 2-4) and AnO 2 m+ (m = 1, 2) ions containing only f electrons. The shielding by f electrons causes the contraction of the An 3+ ions and the magnitude of the actinide contraction along the series to be parallel to that of the lanthanide contraction. Differences in correlation between the energy of 5f and 6d, as well as the 4f and 5d, levels lead to noticeable differences in the magnetic properties and electronic spectra of Ln m+ and An m+ ions. Technetium (4s 2 4p 6 4d 5 5s 2 or 4s 2 4p 6 4d 6 5s 1 ) has oxidation states from +1 to +7, however, those from +4 to +7 are the most stable. Spin-orbit coupling (J) for the An 3+ ions is very strong (2,000-4,000 cm −1 ) and larger that those for the Ln 3+ ions (ca. 1,000 cm −1 ). In contrast to lanthanides, J is comparable with the ligand-field splitting and is no longer a good quantum number. The proximity of the energy of the 5f and 6d orbitals and the population of thermally accessible excited levels lead to the expression for effective magnetic moment μ e = g[J(J + 1)] 1/2 being appropriate for the lanthanides, but not for actinides.
Actinide organometallic complexes are compounds containing an actinide-carbon π-bond, an actinide-carbon σ-bond, or a combination of both. Actinide organometallic complexes are known for all of the early actinide elements (An) from thorium through californium. However, the majority of the reported data is on Th and U organometallic chemistry due to the extremely long half-lives of commercially available 232 Th (in the form of ThCl 4 ) and 238 U (as UCl 4 ) (1.41 × 10 10 and 4.468 × 10 9 years, respectively). Actinides have large metal and ionic radii and, therefore, large coordination numbers (CN) of up to 15. The uranium 6d orbitals play the primary role in covalent bonding between the metal and the ligand, while the 5f orbitals have a secondary role.
In contrast to lanthanides, the actinides have a variety of oxidation states in aqueous solution. The stable oxidation states go from +3 for Ac to +6 for U and Np and then successively decrease to +3 for Am and succeeding elements except No(+2). The maximum and stable oxidation states coincide for Ac, Th, Pa, U, Md, and Lr. Stable states are +7 for Np and Pu, +6 for Am, +4 for Cm, Bk, Cf, Es, and Fm, and +3 for No. The unstable (except for No and Md) oxidation state +2 is known for nearly all actinides in aqueous solution. The An 2+ , An 3+ , An 4+ , AnO 2+ , and AnO 2 2+ hydrated ions are known, which act as Brönsted acids.The An 4+ cations are characteristic for actinides from Th through Cf (U 4+ is readily oxidized) and in the case of Th is the only one existing in solution. Their acidity decreases in the order Pa 4+ >> U 4+ > Pu 4+ > Np 4+ > Th 4+ . The monoatomic ions exist only in very dilute solutions and tend to form polynuclear species when the concentration is increased. The acidity of the An n+ ions depends on the charge and radius of the central atom, so the An 4+ and AnO 2 2+ ions are much stronger acids than An 3+ and AnO 2 + , respectively. The redox behavior of the actinides is complicated by their high radioactivity, leading, in particular, to formation of H 2 O 2 in aqueous solutions.
Moessbauer spectroscopy is a very useful tool to deduce the oxidation state and symmetry of the ligand environment. The gamma-resonance effect is observed for 232 Th, 231 Pa, 238 U, 240 Pu, 243 Am, and especially for 237 Np with a 237 U source. The isomer shifts for Np(VII) compounds are the largest (up to −70 mm/s) and decrease to +30 mm/s for Np(III).

A.2. Actinide Complexes with O-Containing Ligands
Although actinide metal complexes with the simplest inorganic ligands like water and anions were well studied in the previous century, sometimes novel and fresh ideas and calculation results on their structures and properties appear in the available literature. Thus, Car-Parrinello molecular dynamics simulations were used to examine the hydration structures, coordination energetics, and the first hydrolysis constants of Pu 3+ , Pu 4+ , PuO 2 + , and PuO 2 2+ ions were determined in aqueous solution at 300 K. It was found that the hexavalent PuO 2 2+ species are coordinated to five aquo ligands while the pentavalent PuO 2 + complex is coordinated to four aquo ligands. The Pu 3+ and Pu 4+ ions are both coordinated to eight water molecules. The first hydrolysis constants obtained for Pu 3+ and PuO 2 2+ are 6.65 and 5.70, respectively, all within 0.3 pH unit of the experimental values (6.90 and 5.50, respectively) [14]. Among other simple ligands, carbonates and borates have been also studied. Thus, curium(III) is able to form a stable complex in a high ionic strength aqueous solution, in the temperature range of 10-70 °C, as demonstrated recently by a time-resolved laser-induced fluorescence spectroscopy study [15]. Borate complex Cm 2 [B 14 O 20 (OH) 7 (H 2 O) 2 Cl] was synthesized [16] in autoclave using 248 CmCl 3 (3% 246 Cm) and boric acid as the starting materials. Its crystallographic ( Figure 1) and spectroscopic studies provided complementary information about this complex Cm III borate. Both confirmed two distinct sites that are averaged in the crystal structure. It was hypothized that actinide borate compounds yield very distinct chemistry among 5f elements because of the large polarizability of the BO 3 units. This yields unusual bonding with 5f orbitals that is absent in most other ligand systems. Organic ligands are obviously represented by a major number of examples. Thus, the structure of the dimethyl sulfoxide (DMSO)-solvated thorium(IV) ions was studied in solution by EXAFS) and the structure of the solid oxonium bis[nonakis(κO-dimethyl sulfoxide)]thorium(IV) trifluoromethane-sulfonate dihydrate, (H 3 O)[Th((CH 3 ) 2 SO) 9 ] 2 (CF 3 SO 3 ) 9 ·2H 2 O was determined [17]. It consists of two individual nonakis(κ-O-dimethyl sulfoxide)thorium(IV) units, both of which have a tricapped trigonal prismatic configuration, as also found earlier in nonakis(dimethyl sulfoxide)thorium(IV) perchlorate. The DMSO-solvated thorium(IV) ion is nine-coordinate in both solution and the solid state with average Th-O bond lengths of 2.45 Å. On the contrary, the dmso-solvated lanthanoid(III) ions are eight-coordinate.
Actinide carboxylates have been extremely widely studied. Thus, the results on the optical absorption and symmetry of the Np(V) complexes with dicarboxylate and diamide ligands ( Figure 2) are reviewed [18]. It was demonstrated that the optical absorption properties of the Np(V) complexes are governed by their symmetry. The presence of carboxylates could lead to changes in the forms of actinide ions in solution. For example, hydrated actinide(IV) ions undergo hydrolysis and further polymerization and precipitation with increasing pH [19]. The resulting amorphous and partly crystalline oxydydroxides AnO n (OH) 4 − 2n ·xH 2 O can usually be observed as colloids above the An(IV) solubility limit. The aging process of such colloids results in crystalline AnO 2 . The colloids can be avoided in the presence of carboxylates, forming polynuclear complexes in the solution, in a competition in between complexation and hydrolysis. Most of these polynuclear complexes poses a hexanuclear core with general formula [An 6 (μ 3 -O) 4 (μ 3 -OH) 4 ] 12+ terminated by 12 carboxylate ligands. The An(IV) carboxylates show An-An distances which are ~0.03 Å shorter than the An-An distances in AnO 2 like colloids. In addition, the complexation of Eu(III), Am(III) and Cm(III) with dicarboxylate anions with O, N or S donor groups was measured in I = 6.60 mol/kg (NaClO 4 ) at temperatures of 0-60 °C by potentiometry and solvent extraction [20]. It was shown that, despite their endothermic complexation enthalpies, these complexes are stable due to their high complexation entropies.The formation of 1:1:1 ternary complexes of M(EDTA)with the dicarboxylate moiety may favors the formation of several coordination environments of these ternary complex, behaving as bidentate or monodentate coordination modes, depending of the chain length in between both carboxylate coordinating groups (1, for malonate to 4 for adipate). Among particulate carboxylates, uranyl complexes ( Figure 3) with phenylalanine and the analogous ligand phenylpropionate were investigated in aqueous solution by attenuated total reflection (ATR) Fourier transform infrared (FT-IR) spectroscopy [21]. A bidentate binding of the carboxylate group to the actinide ion was observed by the characteristic shifts of the carboxylate modes. The carboxylate functional group was found to be predominant for the binding of the heavy metal ion.Complexes with other organic acids are also common. Thus, the complexation of protactinium(V) by oxalate was studied by a series of methods, indicating the formation of a highly charged anionic complex. The formation constants of PaO(C 2 O 4 ) + , PaO(C 2 O 4 ) 2 − , and PaO(C 2 O 4 ) 3 3− were determined from solvent extraction data by using protactinium at tracer scale (C Pa < 10 −10 M). Complexation reactions of Pa(V) with oxalate were found to be exothermic with relatively high positive entropic variation [22]. The complexation of americium(III) with salicylic acid (Figure 4a) was studied [23] at trace metal concentrations using a 2.0 m long path flow cell for UV-Vis spectroscopy.  Americium(III) has a very low threshold detection limit of 5 × 10 −9 M in water at pH 3.0. It was found that at pH 5.0 in an aqueous 0.1 M NaClO 4 solution, two novel Am(III)-salycylate complexes were formed, as indicated by a red shift of its characteristic absorption band (λ max ) in the UV-Visible spectra. We would like to note that americium evolves in nuclear power plants and contributes to the activity of radioactive waste, so, it has to be considered in radioactive waste management.  Only a few publications concerning the complexation of Am(III) with inorganic and organic ligands are available, especially for the complexation with humic substances [1] and chelating agents. The binary complexation of Am 3+ , Cm 3+ and Eu 3+ with citrate anion was studied at I = 6.60 m (NaClO 4 ) in the temperatures range of 0-60 °C employing a solvent extraction technique with di-(2-ethylhexyl)phosphoric acid/heptanes [24]. Two complexes, MCit and MCit 2 , were formed at all temperatures. Positive enthalpy and entropy values for the formation of both complexes were interpreted as due to the contributions from the dehydration of the metal ions exceeding the exothermic cation-anion pairing. In addition, two types of ligands that have in common three carboxylic groups, namely the citric acid (citric anion, see Figure 4b) and nitrilotriacetic acid, Figure 4c Figure 6) were discussed [25]. In all cases the americium complexes were found to be isostructural with their Nd equivalents.  A uranium-terminal nitride bond length of ∼1.825 Å was revealed. It should be noted that uranium nitride [U;N] x compounds may become an interesting alternative nuclear power source, although there is not too much information about their potential use and properties. It was shown [27], that a terminal uranium nitride complex can be generated by photolysis of an azide precursor (Scheme 2). The transient U,N fragment is reactive and undergoes insertion into a ligand C-H bond to generate new N-H and N-C bonds.   5-and 6-member heterocycles containing N-atoms are also known as ligands in actinide complexes. Thus, the selectivity of N-donor containing ligands such as BTPs (alkylated bis-triazinylpyridines), for actinide complexation in the presence of lantanides, was investigated [29]. NMR studies of an Am (n-PrBTP) 3 3+ complex ( Figure 9) with a 15 N labelled ligand showed that it exhibits large differences in 15N chemical shift for coordinating N-atoms in comparison to both lanthanide(III) complexes and the free ligand. The temperature dependence of NMR chemical shifts observed for this complex indicated a weak paramagnetism. On the basis of this fact and the observed large chemical shift for bound nitrogen atoms, the authors concluded that metal-ligand bonding in the reported Am(III) N-donor complex has a larger share of covalence than in lanthanide complexes. Also, the interaction between neptunium(IV) and room-temperature ionic liquids {BmimCl (1-butyl-3-methylimidazolium chloride), BmimMsu (1-butyl-3-methylimidazolium methylsulfate) and BmimSCN (1-butyl-3-methylimidazolium thiocyanate)} was studied [30]. They might be useful for the recycling of nuclear fuel and the separation of actinides and fission products from waste solutions. Bipyridine adducts are very common [31][32][33][34][35][36] for actinide complexes, as well as in whole in coordination chemistry. As an example, the addition of 2,2'-bipyridine to [U(Tp Me2 ) 2 I] {Tp Me2 hydro-tris-(3,5-dimethylpyrazolyl)borate ligand} resulted in the displacement of the iodide and the formation of the cationic uranium(III) complex [U(Tp Me2 ) 2 (bipy)]I, isolated as a dark-green solid in good yield [37]. These complexes exhibit a slow relaxation of magnetization (energy barrier of 18.2 cm −1 ), with a T c of 4.5 K with frequency dependent magnetic properties, characteristic of single-molecule-magnet behavior (currently only the third example of a uranium compound with such behavior). Also, the solid-state structure of the known complex [Et 4 N][U(NCS) 5 (bipy) 2 ] ( Figure 10) was re-determined and a detailed spectroscopic and magnetic study was performed in order to confirm the oxidation states of both metal and bipy ligand [38]. On the basis of electronic absorption, infrared spectroscopy data, emission spectroscopy and variable temperature magnetic measurements it was suggested that the uranium is in its +4 oxidation state. The bipy ligands are neutral, innocent ligands and not, as would be inferred from just a solid state structure, radical anions. Fitting of the variable-temperature solid-state magnetic data allowed the prediction of polymeric structures for these compounds in the solid state. In addition, thorium(IV) and uranium(IV) macrocycles of Mes 2 (p-OMePh)corrole were synthesized [40] via salt metathesis (Scheme 4) with the corresponding lithium corrole in remarkably high yields (93% and 83%, respectively). Both complexes are dimeric, having two metal centers bridged via bis(μ-chlorido)linkages. In each case, the corrole ring showed a large distortion from planarity, with the Th(IV) and U(IV) ions residing unusually far (1.403 and 1.330 Å, respectively) from the N 4 plane of the ligand.
Distinct amines also form a series of complexes with actinide ions. Thus, the extraction of Th(IV) with N-n-octylaniline and trioctylamine (TOA) in xylene, from an acid aqueous sulphuric acid was reported [41]. The effects of varying the concentration of sulphuric acid, N-n-octylaniline and trioctylamine on the distribution ratio of thorium were studied. Based on the obtained results, the possible extraction mechanism is shown in reactions (1-2). The method can be extended to the analysis of thorium in monazite sand and the gas mantle: where R = C 6 H 5 and R' = R'' = C 8 H 17 .  [42] using both density functional theory and multiconfigurational selfconsistent field methods. It was established that both uranium centers are tetravalent, that the ligands are reduced by two electrons, and that the ground states of these molecules are triplets. Energetically low-lying singlet states are accessible, and some transitions to these states are visible in the electronic absorption spectrum. The computational analysis presented supports the reduction of all α-diimine ligands in these compounds by two electrons, which was demonstrated experimentally. Finally, the fluorinated diarylamines HNPhPh F , HNPh F 2 , HNPhAr F , Ph F = 2,3,4,5,6-pentafluoro-phenyl, Ar F = 3,5-bis(trifluoromethyl)phenyl, were used to prepare homoleptic complexes of uranium(III, IV) ions from UI 4 (Et 2 O) 2 (Scheme 5) [43]. Despite being electronpoor amines with little steric bulk, their coordinated amide ligands exhibited direct control over the coordination environment through a subtle, cooperative interplay of multiple labile F/U dative interactions and favorable arene-arene interactions.
Containing extremely large metal atoms, actinide complexes could have unusual structural characteristics. Thus, the synthesis and studies of the first 15-coordinate complex ( Figure 12) was reported [44]. Reaction of ThCl 4 with four equivalents of sodium N,N-dimethylaminodiboranate, Na(H 3 BNMe 2 BH 3 ), in THF produced [Th(H 3 BNMe 2 BH 3 ) 4 ], which could be isolated as colorless prisms by crystallization from diethyl ether. DFT calculations suggested that this complex may adopt a 16-coordinate structure in the gas phase. The isolated molecule has full D 2d symmetry with a coordination number of 16, but that the crowded nature of the inner coordination sphere is sufficiently destabilizing that molecule distorts and becomes 15-coordinate in the solid state. This is the hightest Werner coordination number for a metal complex reported to the date, and was made possible by combining a very large metal atom with very small ligands.

A.3.2. Actinide Complexes with N,O-and N,S-Containing Ligands
A series of N,O-and some N,S-containing ligands are represented by a series of Schiff bases, iminoacetates and other amino/amido/imino derivatives, among others. Thus, the stability and the associated thermodynamic parameters of the binary and the ternary complexes of trivalent Am and Cm with iminodiacetate (IDA, Figure 13) and with EDTA+IDA, were determined by using a solvent extraction technique for aqueous solutions of I = 6.60 m (NaClO 4 ) at temperatures of 0-60 °C [45]. The endothermic enthalpy and the positive entropy reflected the significant effect of dehydration in the formation of these complexes at high ionic strength. Functionalized bitopic terpyridine(tpy)-diamide N,O-ligands ( Figure 14) were recently developed for the group actinide separation by solvent extraction. In order to acquire a better understanding of their coordination mode in solution, the protonation and the formation of Am(III) and U(VI) complexes with bitopic N,O-containing ligands in methanol/water homogeneous mixtures was studied [46]. When the terpyridine moiety contained amide functional groups, the extracting properties of these ligands was improved, due tochanges in their basicity. Two predominant inner-sphere coordination modes were found from the DFT calculations: one mode where the cation is coordinated by the nitrogen atoms of the cavity and by the amide oxygen atoms and the other mode where the cation is only coordinated by the two amide oxygen atoms and by solvent molecules. Also, it was demonstrated that an uranium(III) tris(amide) complex was capable to selectively couple CO into a linear ynediolate [OCCO] 2− dianion, at ambient conditions (room temperature and atmospheric pressure), in catalytic concentrations (Scheme 6) [47].

Scheme 6.
Coupling and functionalization of carbon monoxide by the trivalenturanium amide to form a uranium-coordinated ynediolate 1, and then an ene-diolate 2.
This compound was able, warming the mixture, to activate a C-H bond of a methyl group across the CC triple bond, forming a new CC bond and generating a functionalized enediolate dianion. As a great contribution of this research for the area of reductive activation reactions of small, traditionally inert molecules such as dinitrogen and carbon dioxide, demonstrated for trivalent uranium complexes, the observed ready interconversion between the U III and U IV oxidation states suggested that catalytic systems based on this coupling and functionaliation are viable. It is notable that the reaction occurs with such a simple coordination compound-an amide that is made from simple commercially available ligands (the precursor amide salt currently costs under €100 per mol). In addition, under mild conditions a simple triamidoamine uranium(III) complex (Scheme 7) can reductively homologate CO and be recycled for reuse [48].  Figure 15) were carried out using IR spectroscopy and single crystal X-ray diffraction [49]. From these analyses, it was determined that complexation takes place through coordination with the carbonyl and pyridine nitrogen moieties. The uranyl complexes showed space groups of Pbca for Et(p)TDPA and P21/n for Et(o)TDPA. Also, the magnetic properties of the triangular molecular nanomagnet [UO 2 L] 3 {L = 2-(4-tolyl)-1,3bis(quinolyl)malondiiminate} were investigated through electron paramagnetic resonance spectroscopy, high-field magnetization and susceptibility measurements [50]. The results showed that [UO 2 L] 3 has a non-magnetic groud state (doublet) due to the chiral arrangement of the uranium magnetic moments to two opposite positions. Quantum tunneling of the non-collinear magnetization, in the presence of a perpendicular external magnetic field results explains its non-axial character of the single-ion crystal field. agent [51]. The data from thermogravimetricanalysis clearly indicated that its decompositionproceeds in four or five steps and theorganic part decomposed in one or twointermediates. The decomposition of the complex ended with metal oxide and carbon residue.    Figure 19. Cont.
These complexes present a wide range of coordination numbers (from 6 to 10), and some of them have antibacterial and antifungal action. In addition, light yellow thorium(IV) six-coordinate complexes were synthesized by reacting Th(IV) nitrate with Schiff bases (Figure 20) derived from 3-substituted-4-amino-5-mercapto-1,2,4-triazole and glyoxal/biacetyl/ benzyl in ethanol [53]. All these complexes are insoluble in DMF and DMSO. The involvement of both C=N groups in the complex formation was suggested, keeping SH groups away from the coordination (Figure 21).  Dioxouranium(VI) and thorium(IV) complexes of ONO-hydrazone ligand derived from 2-hydroxy-5methylacetophenone and 2-furoic acid hydrazide ( Figure 22) were synthesized and characterized [54].  The compounds show semiconductingbehavior as their conductivity increases with increasing temperature. The ligand and its complexes have also been screened for their antibacterial and antifungal activities. The isolated complexes are bright in color, quite air stable, can be stored for long periods, insoluble in water, soluble to very limited extent in common organic solvents but to a considerable extent in DMF and DMSO. Other hydrazone complexes also possess useful applications. For instance, thorium(IV) forms a yellow colored water soluble complex with diacetyl monoxime isonicotinoyl hydrazone reagent DMIH ( Figure 23) in acidic buffer of pH 5.0 with λ max at 352 nm [55]. This simple method using DMIH as a spectrophotometric reagent can be applied for the determination of thorium(IV) in aqueous medium.  Among other recently reported actinide complexes, we note those with amido/amino phenol ligands [58,59] and containing both sulfonate and carboxylate groups [60] .

A.4. Actinide Complexes with Calixarenes
Calixarenes (in particular phosphinoylated calixarenes as p-tert-butylcalix [4]arene, forming stable thorium complexes with 1:1 and 1:2 stoichiometries in organic media [61], or calixarene-based picolinamides and malonamides [62]) feature high coordination ability toward f elements and a great potential for actinide/rare earth separation. In particular, they are applied as as macrocyclic ligands for uranium(VI) [63], showing endo-and exocavity binding in uranyl-calix [6]arene complexes ( Figure 26). Calixarene complexes are mainly used for analytical or extraction/separation purposes. Thus, a new class of calixarene analogues, pillar [5]arenes, having ten diglycolamide (DGA) pendant groups as arms on both rims of the pillar structure, were prepared and their affinity toward Am(III) and Eu(III) evaluated, as potential novel chelating agents for rare-earth and actinide extraction (Scheme 8) [64]. These extractants exhibited excellent separation and extraction efficiency, suggesting its significant potential for nuclear waste remediation. Laser induced fluorescence experiments disclosed strong complexation of the trivalent metal ions with the pillararene-DGA ligands. As a new class of extractants with a framework of pillar conformation that is quite different from the calixarene extractants, pillararene-based diglycolamides may hold potential for the efficient separation of Eu(III) and Am(III) from radioactive liquid nuclear waste. In addition, application of azocalixarene for evaluation of thorium content based on the complex of o-ester tetraazophenylcalix [4]arene (TEAC, Figure 27) with thorium(IV) in acetate buffer solution was offered [65]. This recommended method could be applied for determination of thorium concentration in some monazite ore with high confident results.

A.5. Actinide Complexes with P-Containing Ligands
A few P-containing actinide complexes have been recently reported with classic P-ligands. Thus, (Ph 4 P) 2 UO 2 I 4 . 2NCCH 3 was prepared [66] according to the reaction (3). The redcrystals were soluble in MeCN, but decomposed quickly insolvents such as methanol or THF. It was noted that, whereas UO 2 I 2 . xH 2 O is thermally unstable in the solid state at room temperature, the neutral UO 2 I 2 {OP(NMe 2 ) 3 } 2 , UO 2 I 2 (OPPh 3 ) 2 , and UO 2 I 2 (py) 3 , as well as (Ph 4 P) 2 UO 2 I 4 . 2NCCH 3 , are all stable in the solid state at r.t. Extraction of Am(III) and Cm(III) [67], as well as Np(VI) [68], between tri-n-butyl phosphate solution and molten calcium nitrate hydrate Ca(NO 3 ) 2 . RH 2 O was investigated radiochemically. The extraction reaction of Am and Cm in the Ca(NO 3 ) 2 ·RH 2 O-TBP system is considered to be the same as the reaction in the HNO 3 -TBP system (4). The distribution ratio was found to be inversely related to the water activity (in the range of water content R = 3.5-8.0). This dependence in the hydrate melt changes according to loga H2O = −0.4, which corresponds to R = 5.0. The distribution of Np(IV) between 0.08-4.5 M HNO 3(aq,eqm) and 30% tri-n-butyl phosphate was modelled, accounting for the formation of 1:1 and 1:2 nitrate complexes and Np(IV) hydrolysis in the aqueous phase and the extraction of Np(NO 3 ) 4 (TBP) 2 into TBP [69]. In addition, the role of water in the formation of associates from nanosized complexes of uranium in a supercritical carbon dioxide (SC CO 2 ) medium was studied [70]. It was found experimentally that water in the SC CO 2 exists in the form of microdrops and at a pressure of 10 MPa and a temperature of 40 where M indicates Am or Cm and n indicates the hydration number.
Reaction of the uranium alkyl complex (C 5 Me 5 ) 2 UMe 2 (Scheme 13) with Et 3 N·3HF in toluene in the presence of a donor ligand (pyridine or trimethylphosphine oxide) resulted in gas evolution and the formation of the uranium(IV) difluoride complexes (C 5 Me 5 ) 2 UF 2 (L) (L = NC 5 H 5 , Me 3 P=O) [75]. The fluoride complex (C 5 Me 5 ) 2 UF 2 (NC 5 H 5 ) was reactive against several trimethylsilyl compounds, showing that the U-F bond may provide of a new synthetic tool for the preparation of new functional groups, presently not available from alkoxide and chloride complexes. Recently, a new class of bitopic ligands containing phenantroline and 1,3,5-triazine cores and functionalized with picolinamide groups were prepared. The ligands were able to extract and separate actinides selectively at different oxidation states [76].

B.1. General Concepts on Technetium Complexes
Technetium (Tc) has no stable isotopes; every form of Tc is radioactive. Due to that, there is not almost any natural Tc present on Earth (with the exception of that produced from the spontaneous fission product in uranium ores) and most of it has to be produced synthetically. It was first discovered in 1937 by Carlo Perrier and Emilio Segrè at the University of Palermo by proving that the radioactivity in a molybdenum foil discarded from a cyclotron at Lawrence Berkeley National Laboratory was produced by an element with Z = 43. Technetium short-lived metastable nuclide 99m Tc (T 1/2 6.015 h, γ-irradiator) was later isolated by Segrè and Glean T. Seaborg at Berkeley and it has been widely used until today as a radiotracer in Nuclear Medicine.
In the last 10 years, around 1,000 papers have been published, reporting the preparation and structural characterization of Tc complexes with a wide variety of ligands, or the use of 99m Tc as a radiotracer or radio-emitter in nuclear medicine. Specific applications have been reported in bone scanning, selective imaging of heart, brain, kidney, liver, lungs and other organs, as well as a radiolabeling agent for tumor tissues. Due to its low γ radiation energy (140 keV), short half-life and accessibility, 99m Tc has been the most obvious choice in diagnostic nuclear medicine. Some relatively recent reviews on the state-of-the-art of Tc based diagnostic imaging agents, radiotracers and radiopharmaceuticals [77][78][79][80][81][82][83]. The [Tc(CO) 3 ] + moiety has been widely exploited for the preparation of bioorganometallic compounds for radiopharmacy and the development of in vivo imaging agents [84].
Macrocyclic chelating ligands, such as crown ethers have been also reviewed as they may become useful as radiopharmaceuticals for heart imaging [85]. Radiopharmaceuticals have evolved from simple metal complexes (first generation) with simple ligands, to higher complexity ligands or even ligands derived from biomolecules, mimicking lipophilic and structural properties to increase biocompatibility, biodistribution and tissue recognition specificity. The last two generations have reached clinical application, although chemically are harder targets to achieve ( Figure 29) [80].

B.2. Technetium Complexes with O-Containing Ligands
The chemistry of Tc octahedral oxo complexes has been recently reviewed [86]. The synthesis and characterization of neutral complexes fac-[Tc(CO) 3

First Generation Second Generation
Third Generation the bisphosphine complexes of curcumin was reported, making these compounds potentially useful for pharmacological uses. Antibiotics such as ofloxacin, sitafloxacin, sparafloxacin, norfloxacin, garenoxacin, trovafloxacin, ciprofloxacin and norfloxacin, have been explored as ligands to prepare technetium-99m tricarbonyl complexes ( Figure 30). These complexes have been tested against S. aureus as a bacterial infection model both in vitro (bacterial cultures) and in vivo (infected rats). All these molecules share a common fluoroquinolone skeleton. Fluoroquinolones are broad-spectrum antibiotics with good oral absorption and excellent bioavailability. They possess a carboxylic acid function at the 3-position and a carbonyl oxygen atom at the 4-position, becoming potentially good bidentate chelating ligands toward metal ions. Preparation of the dithiocarbamate derivative in some cases was explored, in order to use the-CS 2 fragment as a coordinating moiety toward the 99m Tc ion. Good biodistribution and high accumulation in the infected region make these complexes suitable for applications as radiotracer for infection imaging [88][89][90][91][92][93][94][95][96]. Doxycycline, another antibiotic used for the treatment of several infections and part of the tetracycline class, has been also labeled with 99m Tc to explore its use as a radiotracer for infection imaging [97]. It also has several chelating moieties, which makes it a versatile ligand for coordination to metal ions ( Figure 31). Stability, sterility and in vivo distribution in an animal model (rats) were performed, finding high uptake in bacterial infection site, yielding promising results.

B.3. Technetium Complexes with N-, O-, P-or S-Containing Ligands
Several technetium coordination complexes with chelating ligands (bi-, tri-and tetradentate) containing at least a nitrogen atom have been reported in the past decade. These ligands seek to overcome problems related to the use of the Tc(I) core as a radiotracer in a metal complex, as they need to be hydrophilic. However, most of the chelating agents are lipophilic, contributing to a poor pharmacokinetic performance. Several of those chelating ligands, coordinate to different 99m Tc targets, such as [Tc(CO) 3 ] − or [TcO 3 ] + . For example, the reaction between [TcO 4 ] − and the strong Lewis acids benzoyl chloride and BF 3 . OEt 2 , was explored for the synthesis of complexes containing the [TcO 3 ] − core with ligands such as 2,2'-bipyridine, 1,10-phenantroline, di-1H-pyrazol-1-yl acetate, bis(3,5-dimethyl-1H-pyrazol-1-yl)acetate, 1,1,1-methanetriyltris(3,5-dimethyl-1H-pyrazole), and their 99 Tc NMR spectra recorded; their rhenium analogues were also structurally characterized [98] . Water soluble 99m Tc complexes with sugar-substituted bipyridine complexes obtained from the reaction of 4,4'-dibromomethyl-2,2'-bipyridine with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylthiol, 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosylthiol or 2,3,4,6-tetra-O-acetyl-α-D-thioacetylmannopyranoside were obtained and fully characterized ( Figure 32). The complexes are stable for several hours in the presence of coordinating ligands (histidine), showing partial ligand-exchange after 24 h [99]. In other work, the preparation of 99m Tc complex with a bidentate 6-(pyridine-2-methylimine)-4-[3-bromophenyl)amino]-quinazoline ligands was reported recently [100]. This metal complex was explored for use as a biomarker for EGFR positive tumors, observing inhibition of the EGFR autophosphorylation. Finally, a series of myocardial perfusion imaging agents was prepared using different mono-and bidentate ligands (imidazole, 1,10-phenanthroline, 2,2-bipyridine) labeled with tricarbonyl-99m Tc were reported and fully characterized [101]. Dihydropyrimidinone [102] and bemzamidoxime [103] derivatives were synthesized and their 99m Tc complexes prepared using stannous chloride as reducing agent. Their potential uses are as radiotracers for infections (E. coli) or lung radioimaging, showing good biodistribution and stability. The complexes were prepared from sodium pertechnate or 99m Tc-glucoheptonate, with high radiochemical yields. Other 99m Tc complexes with tridentate and tetradentate ligands containing at least a nitrogen donor atom, were prepared, characterized and their use as biomedical radiotracer agents explored. Figures 33  and 34 show the common chelating groups used to tri-coordinate and tetra-coordinate technetium into a complex, respectively. Tables 1 and 2 Table 2.  Lys-NHCONH-Glu inhibitor II Imaging of prostate specific membrane antigen (PSMA) [105] Cyclo-[Arg-Gly-Asp-D-Tyr-Lys(PZ)] I Integrin receptors in tumor cells and neovasculature [106] Ala-NLe-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 I Imaging of melanocortin type 1 receptor (MC1R) in melanoma tumors [107] Lysine aminoacid derivatives conjugated to octreotide III Tumor imaging [108] 16-mer peptide nucleic acid sequence H-A GAT CAT GCC CGG CAT-Lys-NH 2 I Radioimaging human neuroblastoma cells [109] Diethyl phosphonate, phosphoric acid and bisphosphonic acid derivatives I Bone imaging [110] L-Arg conjugates I Monitoring of in vivo activity of inducible nitric oxide synthase (iNOS) [111] Lisinopril II Imaging of angiotensinconvering enzyme (ACE) for hearth failure monitoring [112] Insulin II Tracing insulin biochemistry in vivo [113] Aliphatic or aromatic ethers I, II Cardiac imaging [114] Glu-urea-Lys, Glu-urea-Glu I, II Imaging of prostate specific membrane antigen (PSMA) [115] DNA intercalator and bomesin analogue II Imaging gastrin releasing peptide receptor (GRPr) and Auger therapy [116] Duanidino, N-hydroxyguanidine, Nmethylguanidine, N-nitroguanidine or S-methylisothiurea moieties II iNOS visualization [117] Ac-DEVD-R110-D-SAAC-Fmoc II Monitoring of apoptosis [118] Pamidronate and alendronate I Bone imaging [119] Bile acid I Radiopharmaceuticals for hepatobiliary diseases, liver tumor and intestinal cancer [120] N,N,O Pyridyl-tert-nitrogen-phenol ligand IV Radiolabeling agents [121] Glucosamine IV Radiolabeling of glucose biochemistry [122,123] 4-Nitrobenzyl moiety IV Bioreductive diagnostic radiopharmaceutical [124] 15-[N-(hydroxycarbonylmethyl)-2picolylamino)pentadecanoic acid V Radiotracer for evaluation of fatty acid metabolism in myocardium [125] Estradiol VI Imaging agent for estrogen receptor in tumor cells [126] [149] Tridentate complexes, with PNP chelating ligand as shown in Figure 35, have been reported. A couple of works reported the preparation of a lipophilic cationic 99m Tc-DBODC complex (DBODC = dimethoxypropylphosphinoethyl)ethoxyethylamine) which was investigated as myocardial imaging agent [150][151][152]. The impact of bidentate chelators on lipophilicity, stability and biodistribution in Sprague-Dawley rats of a cationic 99m Tc-nitrido complex with a similar PNP tridentate ligand was studied; it was found that the metal complex was a very promising candidate for further preclinical studies in other animal models [153]. In a related work, a dithiocarbamate metronidazole derivative, potassium 2-(2-methyl-5-nitro-1H-imidazolyl)ethyldithiocarbamate, was synthesized and its complex with technetium was prepared in order to evaluate its potential as a tumor hypoxia marker [154]. The functionalization of the PNP tridentate ligand with fatty acid ligands was also explored, for being used as labelling agents to follow myocardial metabolism. The fatty acid derivatives were attached to one terminus of the carbon chain into a dithiocarbamate fragment [155]. Other metal complexes with different donor atoms were also reported. For example, carboxyl-rich thioether tridentate ligands were used to form technetium complexes and were used to measure effective renal plasma flow in rats. The complexes were formed from the reaction among [Tc(CO) 3 (H 2 O) 3 ] + at 70 °C and carboxymethylmercaptosuccinic acid or thiodisuccinic acid [156]. A bulky alkylphosphino-thiol bidentate ligand was used to form a complex with technetium; when reacted in the presence of a dithiocarbamate it was found that stable dissymmetrical mixed-substituted complexes were formed [157]. It was reported that these complexes may have potential applications as radiopharmaceuticals for imaging and therapy. Finally, a technetium-diethyl dithiocarbamate (DEDT) complex was prepared by a two-step procedure and studied as a potential brain radiopharmaceutical for brain imaging. Biodistribution in mice indicate that the complex is able to penetrate through the blood-brain-barrier (BBB), suggesting it may be potentially useful as a brain perfusion tracer [158].
From 2007 to the date, several research groups have explored the preparation of Tc(I) complexes based on ligands obtained by click chemistry. Click chemistry provides a useful synthetic tool for the preparation of multifunctional radiopharmaceuticals for several potential biomedical applications. With that in mind, Huisgen click chemistry and monodentate phosphine ligands have been used for biomolecule incorporation on 99m Tc complexes [159]. Bombesin analogues were prepared by a "click approach", using Cu(I)-catalyzed cycloaddition to obtain a new series of triazole-based chelating systems for labeling 99m Tc(CO) 3 moieties, which presented good biodistribution and improved tumor detection [160,161]. A bidentate ligand containing a bioactive pharmacophore, (2methoxyphenyl)piperazine, has been prepared by this synthetic strategy, to further obtain a lipophilic technetium complex, potentially useful as a CNS imaging agent [162]. In other work, by the same group, the first example of a tridentate ligand obtained by click chemistry, was reported, and it was used to form a 99m Tc(CO) 3 complex for radioimaging [163]. Finally, a tetradentate ligand able to form Tc X X N R 1 P P R 2 R 2 R 2 R 2 N Tc(V) complexes was obtained by a "click-to-chelate" strategy, and its ability for being used as a in vivo radiotracer explored successfully [164].

B.4. Technetium Organometallic Complexes
Technetium organometallic compounds were prepared as potential use for imaging and cancer therapy. A ferrocenyl triarylbutane derivative labeled with 99m Tc by metal exchange reaction with [TcO 4 ] − was synthesized and its in vivo biodistribution was determined in female Wistar rats, with promising results [165]. Causey and coworkers reported the synthesis and evaluation of mono-and di-aryl technetium metallocarborane derivatives [(RR'C 2 B 9 H 9 )Tc(CO) 2 (NO)] (R = p-PhOH, R' = H) as a new class of probes for estrogen receptors [166]. The technetium-carborane was generated using a cage isomerization process, in high yield (84%). In a closely related research, a functionalized carborane complex with 99m Tc core, prepared by a microwave assisted approach, was studied for potential use as organometallic probes for in vitro and in vivo correlated imaging [167]. In a different work, long chain fatty acid analogs, labeled with 99m Tc were prepared by linking at the omega-position of pentadecanoic acid acyclopentadienyltricarbonyltechnetium fragment [168]. The novel, lipophilic complex, was injected into rats and it was found to accumulate in myocardial tissue. It is a promising radiotracer for myocardial metabolism monitoring. In 2007, Miroslavov et al. developed a reasonable yield synthesis to prepare [Tc(CO) 5 X] (X = Cl − , Br − ). From this compound, they were able to prepare the t-butyisocyanide and tripheynlphosphine derivatives, by halide substitution [169]. The preparation of a new cytectreene of general formula RCpTc(CO) 3 (R = C 6 H 5 NHCO, Cp = cyclopentadyenyl) was prepared from N-phenylferrocenecarboxamide. The 99m Tc complex was lipophilic enough to cross the BBB, making it an interesting base for the development of brain perfusion imaging agents [170]. Finally, in the quest for novel organometallic 99m Tc imaging agents, water stable N-heterocyclic carbine complexes were prepared by the reaction of [TcO(glyc) 2 ] − (glyc = ethyleneglycolato) with 1,3-dimethylimidazoline-2-ylidene, 1,1'-methyelen-3,3'-dimethyl-4,40-dimidazoline-2,2'-diyldene and 1,1'-methylene-3,3'-diethyl-4,4'-diimidazoline-2,20-diyldene in THF. Bidentate NHCs complexes were water-stable over a broad pH range, paves the way for the design of novel radiopharmaceuticals based on NHC complexes [171]. Figure 36 shows some selected examples of these technetium organometallic compounds.

B.5. Applications of Technetium Labeling to Nanomaterials
In the dawn of nanoscience and nanotechnology, radiolabeled nanomaterials are becoming a common practice in the field. Multifunctional nanomaterials can simultaneously be used for diagnostic and therapy in a relatively young field called theranostics [172]. Then, radiotracers incorporated into nanomaterials make them useful as novel medical imaging agents, with the ability to penetrate through several biological barriers, fine tune their selectivity to specific targets and to modulate their biodistribution. This field is still young, but it can be prognosticated that in the future more advances and contributions will be available in the scientific literature. For example, PLA-PEG (polylactic acidpolyethylene oxide) nanocapsules labeled with 99m Tc-HMPAO (hexamethylpropylene-amine oxime) were prepared and their physical properties (size, size distribution, homogeneity) were determined by photon correlation spectroscopy and zeta potential by laser Doppler anemometry [173]. The results suggest that the radiolabeled nanocapsules were more stable against label leakage in the presence of proteins and could have better performances as radiotracers in vivo. In another work, polylactide-coglycolide (PLGA) nanoparticles containing chloramphenicol were obtained by emulsification solvent evaporation, using polyvinylalcohol (PVA) or polysorbate-80 (PS-80) as surfactants. The nanoparticles were radiolabeled with 99m Tc by stannous reduction and their biodistribution after intravenous administration in mice was followed. Brain uptake was high, with low accumulation in bone marrow. The results are promising for the use of these systems for drug delivery and controlled release agents [174]. The use of technetium as radiolabeling agent to study the biodistribution of self-assembling protein nanoparticles allowed to determine their pharmacokinetic properties in vivo, in order to evaluate their usefulness as vaccine platforms [175]. In another work, pullulan acetate nanoparticles (PAN) were prepared by dialysis and radiolabeled with 99m Tc with a 98% efficiency. The hydrophobic, spherical particles, with seizes in the range from 50 to 130 nm, were stable in aqueous suspensions and may be efficient for intratumoral administration [176]. Dendrimers belong to a special class of nanostructured materials with growing interest for pharmaceutical and biomedical use. Partially acetylated generation five polyamidoamine (PAMAM) dendrimer (G5-Ac) was reacted with biotin and 2-(pisothiocyanatobenzyl)-6-methyl-diethylenetriamine-pentaacetic acid and avidin to form a dendrimeravidin conjugate, which was radiolabeled with 99m Tc. The nanostructured conjugate was evaluated for in vitro cellular uptake and biodistribution [177]. Finally, the preparation, characterization and biodistribution of letrozole loaded PLGA nanoparticles in tumor bearing mice was recently reported [178]. The PLGA nanoparticles were prepared by the solvent evaporation technique and characterized by TEM and DLS; radiolabeling with technetium was achieved with high efficiency and biodistribution indicate that the letrazole loaded nanoparticles present higher tumor uptake than usual drug delivery vehicles.

Conclusions
During the last 7-10 years (2007-2014), nearly 2,500 research papers have been published containing theoretical and experimental results on the chemistry of actinide and technetium metallic elements. They have revealed novel and interesting physical and chemical properties of their coordination and organometallic chemistry, in particular revealing fundamental information on their unusual molecular and electronic structures and reactivity. For instance, the highest observed Werner coordination number (15) has been found in a Th complex with formula [Th(H 3 BNMe 2 BH 3 ) 4 ].Most of these complexes are formed by chelating, polydentate ligands containg O-and N-donor centers, but several heteroatom mixed ligands containing S-, P-ligands have been also explored. The solid state structures of these compounds has been extensively studied by single crystal X-ray crystallography in order to determine the variable and unique coordination modes of the several functional groups included into the ligands in order to coordinate toward the radioactive metal atoms. Talking about their usefulness, the design of complex, chelating, multidentate ligands can be applied in the processes of nuclear waste remediation (i.e., recycling of nuclear fuel and the selective separation of actinides and other fission products from waste solutions). Applications in analytical chemistry as specific ligands forrecongnition and determination of actinides in solutions has been also reported. Their rich and unique organometallic chemistry has also been heavily explored, and without any doubt still will keep showing in the future novel compounds with extraordinary properties and structures. Their bioactive properties, resulting from the radioactive and spontaneous emission of alpha or beta particles and/or gamma radiation, have been also explored for the design of novel antimicrobial and anti-fungalcompounds. In particular, the chemistry of technetium-99m ( 99m Tc) short-lived metastable nuclide has been exploited for the preparation of metal complexeswith lipophilic ligands for brain and heart radioimaging, asa well as for radiolabeling antibiotics, steroids, peptides and other bioactive molecules, not only for tracking their fate into the organisms, which is of great help for pharmaco-kinetic studies or the understanding of metabolic pathways, but also for the preparation of novel in vivo imaging agents for diagnostics and therapy. A very promising field for the application of 99m Tc or Ac complexes or radiotracers is in the very explosive field of nanoscience and nanotechnology, in particular to the use of nanomaterials in health (nanomedicine). Their application for monitoring the biodistribution, accumulation and metabolism of radiolabeled nanomaterials designed for drug transport and controlled releasing, theranostic agents (simultaneous diagnostics and therapy agents in one material), medical imaging and other related biomedical applications, without any doubt will result in many interesting contributions in the near and far future, which will enrich the already extraordinary broad and productive field of research of radioactive metal complexes.