Supramolecular Assembly Formation of Ferrioxamine B and Its Al(III), Ga(III), and In(III) Analogues with Dicyclohexano-18-Crown-6 in Chloroform

We have shown that the crown ether dicyclohexano-18-crown-6 recognizes the terminal amine group of deferriferrioxamine B (H4DFB+) and its Al(III), Ga(III), Fe(III), and In(III) complexes (MHDFB+) by host-guest complex formation. Host-guest formation constants for these supramolecular assemblies in chloroform at 25 °C were determined as follows: log Ka(H4DFB+) = 4.56, log Ka(A1HDFB+) = 3.48, log Ka(GaHDFB+) = 3.59, log (FeHDFB+) = 3.67, log Ka(InHDFB+) = 3.92. Chloroform extraction equilibrium constants (Kex) for the extraction of the MHDFB+ complexes and H4DFB+ in the presence of picrate anion by crown ether were determined as well as distribution constants (Kd) between a chloroform and aqueous phase in the absence of crown ether: log Kex(H4DFB+) = 2.89, log Kex(A1HDFB+) = 2.43, log Kex(GaHDFB+) = 2.84, log Kex(FeHDFB+) = 3.05, log Kex(InHDFB+) = 3.46; log Kd(H4DFB+) = -1.66, log Kd(AlHDFB+) = -1.05, log Kd(GaHDFB+) = -0.75, log Kd(FeHDFB+) = -0.62, log Kd(InHDFB+) = -0.46. In the series InHDFB+, FeHDFB+, GaHDFB+, and A1HDFB+ there is increasing hydration in the second coordination shell, as suggested by a linear relationship between log (Ka,Kex,Kd) and 1/ri (ri = M3+ radius) and M(H2O)63+ hydration enthalpy (ΔHhyd). which consequently increases hydrophilicity (decreases Kd) and increases steric hindrance to crown ether host-guest complex formation (decreases Ka). Correspondingly, the chloroform extraction constants (Kex = Kd·Ka), which depend on chloroform/water distribution (Kd) and host-guest complex formation (Ka), decrease in the same sequence. We conclude that the protonated amine of the free ligand H4DFB+ and its metal complexes provides a recognition site through formation of a supramolecular assembly with a crown ether. Second coordination shell effects (hydrophilicity) provide a mechanism to discriminate between different M(III) complexes of deferriferrioxamine B. The low Kd value obtained for deferriferrioxamine B distribution between the hydrophilic and lipophilic phase is consistent with previous reports concerning the therapeutic use of this ligand to remove intracellular iron from patients with iron overload. © 1994, American Chemical Society. All rights reserved.

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