Triaza-macrocyclic complexes of aluminium, gallium and indium halides: fast 18F and 19F incorporation via halide exchange under mild conditions in aqueous solution

Rapid and complete fluorination of the complexes [MCl3(L)] (L = Me3-tacn, BzMe2-tacn, M = Al, Ga, In) occurs at room temperature via reaction of a MeCN solution of the complex with 3 mol. equivs. of KF in water. The Ga and In complexes are also readily fluorinated using R4NF (R = Me or nBu) in MeCN solution, whereas no reaction occurs with the Al species under these conditions. The distorted octahedral fac-trifluoride coordination at M is confirmed in solution by multinuclear (19F, 27Al, 71Ga and 115In) NMR spectroscopic studies, leading to sharp resonances with 19F-71Ga and 19F-115In couplings evident. The [MF3(L)] are extremely stable in aqueous solution and at low pH; they crystallise as tetrahydrates, [MF3(Me3-tacn)]·4H2O, with extended H-bonding networks formed through both F···H-O and O···H-O contacts. [InF3(BzMe2-tacn)]·1.2H2O also shows intermolecular F···H-O hydrogen bonding contacts. The prospects for developing this coordination chemistry further to take advantage of the high metal-fluoride bond energies to enable rapid, late-stage fluorination of large macromolecules under mild conditions for PET imaging applications in nuclear medicine are discussed. This work also demonstrates that F-18 radiolabelling to form [F-18] [GaF3(BzMe2-tacn)] is effected readily at room temperature in aqueous MeCN over 30-60 mins on addition of 2.99 mol equivs. of [19F]-KFaq and 0.4 mL [18F]-KFaq (100 – 400 MBq) to [GaCl3(BzMe2-tacn)] with ca. 30% incorporation

Hydrothermal synthesis of Group 13 metal trifluoride complexes with neutral N-donor ligands

The reactions of the hydrated Group 13 fluorides, MF3·3H2O (M = Al, Ga or In) with 2,2?:6?,2??-terpyridyl, 2,2?-bipyridyl or 1,10-phenanthroline under hydrothermal conditions (180 °C/15 h) produced high yields of the complexes [MF3(terpy)]·3H2O, [MF3(bipy)(OH2)]·2H2O and [MF3(phen)(OH2)]. X-Ray crystal structures of [M?F3(terpy)]·3H2O (M? = Al or Ga), [M?F3(bipy)(OH2)]·2H2O and [GaF3(phen)(OH2)] show that all of them contain distorted octahedral geometries at the metal with mer-trifluoride coordination. Extensive H-bonding (FH–OH) links the molecules. The complexes have been further characterised by microanalysis, IR, 1H, 19F{1H} and 27Al NMR spectroscopy. In contrast, reactions of the trifluorides with the acyclic triamine, N,N,N?,N?,N??-pentamethyldiethylenetriamine, under similar hydrothermal conditions results in cleavage of the triamine and ring-closure to form the 1,1,4-trimethylpiperazinium cation, [?Me2N(CH2)2NMe(CH2)2]+, with fluorometallate anions, and confirmed by X-ray analysis of [?Me2N(CH2)2NMe(CH2)2]2[Al2F8(OH2)2]·2H2O. The strongly H-bonded [GaF3(terpy)]·3H2O was also obtained by Cl/F exchange from [GaCl3(terpy)] and [NBu4]F or [K(2,2,2-crypt)]F. Crystallisation of a mixture of [NH4][PF6] and [GaF3(terpy)]·3H2O from aqueous solution produced the edge-bridged cationic complex, [{Ga(terpy)F}2(?-F)2][PF6]2. The synthesis of the more sterically bulky [GaCl3(tBu3-terpy)] (tBu3-terpy = 4,4?4??-tris-tBu-2,2?:6?,2??-terpyridyl) and the crystal structure of [GaCl2(tBu3-terpy)][GaCl4], which contains a trigonal bipyramidal cation, are also reported

Radiofluorination of a pre-formed gallium(III) aza-macrocyclic complex: towards next-generation positron emission tomography (PET) imaging agents

As part of a study to investigate the factors influencing the development of new, more effective metal-com-plex-based positron emission tomography (PET) imaging agents, the distorted octahedral complex, [GaCl(L)]·2HO has been prepared by reaction of 1-benzyl-1,4,7-triazacyclono-nane-4,7-dicarboxylic acid hydrochloride (HL·HCl) with Ga(NO)·9HO, which is a convenient source of GaIII for reactions in water. Spectroscopic and crystallographic data for [GaCl(L)]·2HO are described, together with the crystal structure of [GaCl(L)]·MeCN. Fluorination of this complex by Cl/ F- exchange was achieved in high yield by treatment with KF in water at room temperature over 90 minutes, although the reaction was complete in approximately 30 minutes if heated to 80 °C, giving [GaF(L)]·2HO in good yield. The same complex was obtained by hydrothermal synthesis from GaF·3HO and LiL, and has been characterised by singlecrystal X-ray analysis, IR, 1H and 19F{1H} NMR spectroscopy and ESI + MS.Radiofluorination of the pre-formed [GaCl(L)]·2 HO has been demonstrated on a 210 nanomolar scale in aqueous NaOAc at pH 4 by using carrier-free F , leading to 60-70% F-incorporation after heating to 80 8C for 30 minutes. The resulting radioproduct was purified easily by using a solid-phase extraction (SPE) cartridge, leading to 98-99% radiochemical purity. The [Ga F(L)] is stable for at least 90 minutes in 10% EtOH/NaOAc solution at pH 6, but defluorinates over this time scale at pH of approximately 7.5 in phosphate buffered saline (PBS) or human serum albumin (HSA). The subtle role of the Group 13 metal ion and coligand donor set in influencing the pH dependence of this system is discussed in the context of developing potential new imaging agents for PET

[GaF3(BzMe2-tacn)] – a neutral ‘metalloligand’ towards alkali metal and ammonium cations in water

The neutral complex, [GaF3(L)] (L = 1-benzyl-4,7-dimethyl-1,4,7-triazacyclononane, BzMe2-tacn), acts as a ‘metalloligand’ to Na+, K+ and [NH4]+ cations in aqueous solution, forming supramolecular assemblies containing significant Na/K–F and H3N+H⋯F coordination. κ1-[BF4]− and κ2-[PF6]− coordination is also evident to Na+ and K+, respectively

Complexes of aluminium, gallium and indium trifluorides with neutral oxygen donor ligands: synthesis, properties and reactions

The MF·3HO (M = Al, Ga or In) dissolve in hot dimethylsulfoxide (dmso) to form [MF(OH)(dmso)]; further dmso is not incorporated even after prolonged reflux. The X-ray structure of [GaF(OH)(dmso)] shows mer fluorides and trans OH ligands. The [GaF(OH)(dmso)] reacts with Metacn (1,4,7-trimethyl-1,4,7-triazacyclononane) or 2,2′-bipyridyl to give good yields of [GaF(Metacn)]·xHO and [GaF(bipy)(OH)]·2HO at room temperature, previously obtained from GaF·3HO by a hydrothermal route. [MF(OH)(dmso)] (M = Al or Ga) do not react with RPO (R = Me or Ph) in CHCl or MeOH, but with pyNO (pyridine-N-oxide), the products were [AlF(OH)(pyNO)] and [GaF(OH)(pyNO)]·pyNO·HO. The structure of the latter shows equal numbers of the geometric isomers with mer-trans and mer-cis geometries, as well as lattice pyNO and HO. Pentamethyldiethylenetriamine (PMDTA) and [GaF(OH)(dmso)] react to produce the zwitterion [GaF(PMDTAH)]·2HO, which contains κ-PMDTA with the 'free' NMe group protonated to balance the charge of the GaF unit. Crystals of [⊂MeN(CH)NMe(CH)][GaF(OH)]·HO containing a 1,1,4-trimethylpiperazinium cation, were obtained as a minor by-product. The anion is an edge-shared fluoride-bridged dimer, with the coordinated water ligands arranged anti. Attempts to prepare complexes with phosphine or thioether ligands by Cl/F exchange from the corresponding chloro-complexes with [NMe]F were unsuccessful, halide exchange being accompanied by liberation of the soft donor ligand. X-ray structures are also reported for [MeNH][trans-GaF(OH)] and [AlCl(OAsPh)]