Covalently Bonded Fluorine as a σ-Donor for Groups I and II Metal Ions in Partially Fluorinated Macrocycles

Abstract

Novel fluoro cryptands and fluoro crown ethers were synthesized in good yields in the reactions of 1,3bis(bromomethyl)-2-fluorobenzene with diaza-18-crown-6 [the resulting two macrocycles are abbreviated as FN 2 O 4 (1 + 1 product) and (FN 2 O 4 ) 2 (2 + 2 product)], diaza-15-crown-5 [product abbreviated as FN 2 O 3 ], aza-(3n)-crown-(n) (n ) 4, 5, 6) [F(NO 3 ) 2 , F(NO 4 ) 2 , F(NO 5 ) 2 ], and the potassium salts of tetraethyleneglycol [FO 5 ] or pentaethylene glycol [FO 6 ] and in the reaction of 1-(bromomethyl)-3-methyl-2-fluorobenzene with aza-15-crown-5 [FNO 4 ]. The analogous reactions of 1,3-bis(bromomethyl)benzene with diaza-18-crown-6 [HN 2 O 4 ], diaza-15-crown-5 [HN 2 O 3 ], and the potassium salt of tetraethylene glycol [HO 5 ] led to the isolation of closely related fluorine-free cryptands and crown ethers. The 19 F NMR resonances of the fluoro macrocycles shift upon complexation of metal ions by between ∆δ ) -18.2 ppm and ∆δ ) +8.5 ppm relative to those of the respective free ligands. To explain the unexpected high-field shifts ∆δ of most metal complexes, a qualitative model is proposed which considers conformative rearrangements of the oxyethylene chain to be mainly responsible for the ∆δ values, with the deshielding effect of the positive charge of the metal ions being smaller in most cases. It was demonstrated that the 1 J CF coupling constants can be used to gauge the strength of metal-fluorine interactions since the values for 1 J CF range from 253 Hz (FN 2 O 4 ) to 238.5 Hz (Li + ‚FN 2 O 4 ), 242 Hz (Na + ‚FN 2 O 4 ), 246.5 Hz (K + ‚FN 2 O 4 ), and 249 Hz (Rb + ‚FN 2 O 4 ). The larger the metal ion the less it is able to migrate into the cavity and contact the C-F unit. The stability constants of the metal complexes of the fluoro macrocycles and their fluorine free relatives were determined by picrate extraction experiments and NMR competition experiments. It is evident from both investigations that the fluorine-containing macrocycles form more stable metal complexes than the analogous fluorine free systems. This is taken as a proof for C-F to metal ion σ-donor bonds. It is significant that this stabilizing effect is only observed when the radii of the metal ion and macrocyclic cavity are complementary, since only then can the metal ion contact the C-F unit. The crystal structures of FN 2 O 3 and the metal complexes were determined. In the solid state structures of all metal complexes with the exception of Na + ‚FNO 4 , short metalfluorine distances are observed, which are approximately as long as the respective metal-oxygen distances and much shorter than the metal-N distances [Li + ‚FN 2 O 3 : Li + illustrates the importance of fluorine coordination since this interaction is required to position the metal ion within the center of the cavity, whereas in Li + ‚HN 2 O 3 the cation is located on the outer edge of the cavity, completing its coordination sphere with one additional molecule of water.

The Coordination Chemistry of the CF Group of Fluorocarbons: Thermodynamic Data and Ab Initio Calculations on CF-Metal Ion Interactions

“…The fluorine-free cryptands HN 2 O 3 and HN 2 O 4 were synthesized according to the literature procedure. [7] The heptafluorobutyrates of the alkaline earth cations were prepared by the addition of solid alkaline earth metal hydroxides to a concentrated aqueous solution of heptafluorobutyric acid (Aldrich) until no more dissolution of the hydroxide could be observed. The reaction mixture was filtered, and the volatile substances evaporated.…”

“…[6] Apart from X-ray crystal structure determinations, NMR spectroscopy and picrate extraction were used to investigate the nature of CF ± metal ion interactions. [7] Erker et al, [8] Marks et al, [9] and others [10] discovered that the CF groups of fluorinated phenylborate ligands can allow hemilabile coordination of cationic zirconocenes. Erker et al suggested that such weak contacts might be used to reversibly control the catalysis of Ziegler ± Natta-type olefin transformations.…”

“…Physical properties as described previously. [7] Crystal structure determination. Single crystals of FN 2 O 4 -Ba(ClO 4 ) 2 were prepared by allowing diethyl ether to slowly diffuse into a solution of the complex in acetonitrile.…”

VatuximabTM: Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

“…Plenio and Diodone have also reported fluorocrown ethers (Table 5), which exhibit chemical shift response upon binding Ca 2þ [314]. Of course, calcium could potentially be analyzed directly by 43 Ca NMR, however, its natural abundance is <0.2%, its sensitivity is <1% that of 1 H, and being quadrupolar, it is liable to extensive line broadening [59].…”

Breast Cancer Gene Therapy: Development of Novel Non-Invasive Magnetic Resonance Assay to Optimize Efficacy

“…These investigators have tumor oxygenation as part of therapeutic planning. Patients also reported a series of fluorocyclophanes and fluoro crown could be stratified according to baseline hypoxia to receive ethers to explore specific cation binding (e.g., K+, Li+, Na+, adjuvant interventions designed to modulate P 0 2, or more Ba 2 +, Sr 2 +, Ca 2 +, and associated chemical shifts [136,148]. intense therapy as facilitated by IMRT (Intensity Modulated Radiation Therapy).…”