Copper(II) interaction with mono-, bis- and tris-ring N3O2 macrocycles: synthetic, X-ray, competitive membrane transport, and hypochromic shift studies.

New N-phenyl (L(1)), azo-coupled (L(2)), and tri-linked (L(3)) substituted derivatives of a parent dibenzo-N(3)O(2) macrocycle, 1,12,15-triaza-3,4:9,10-dibenzo-5,8-dioxacycloheptadecane (L(4)), have been synthesized. Competitive seven-metal transport studies across a bulk chloroform membrane employing an aqueous source phase containing equal molar concentrations of Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Ag(I), and Pb(II) as their nitrate salts have been performed using both L(1) and L(3) as the ionophore, with the results discussed in terms of those obtained previously for related mono-ring (L(5)) and di-linked (L(6)) macrocyclic systems. Sole transport selectivity for Cu(II) was observed in each case. On a per macrocyclic cavity basis the tri-linked analogue L(3) gave less efficient Cu(II) transport than its monomeric or di-linked analogues. At least in part, this may reflect the tendency of tri-linked derivative L(3) to form a 2:1 complex (metal/ligand) with Cu(II) under the conditions employed; such a stoichiometry was demonstrated to occur in acetonitrile using both spectrophotometric titration and Job plot procedures. The azo-coupled derivative (L(2)) yields a red solution (lambda(max) = 495 nm, epsilon(max) = 23000 M(-1) cm(-1)) and undergoes significant hypochromic metal-induced shifts (Delta lambda(max) = 54-174 nm) on metal addition. Cu(II) induces the largest shift (Delta lambda(max) = 174 nm), corresponding to a color change from red to pale-yellow. The X-ray structures of red L(2) x HNO(3) together with its Cu(II) complexes, [Cu(L(2))NO(3)]NO(3) x CH(2)Cl(2) (6) (pale-yellow) and [{Cu(L(2))}(2)(mu-OH)(2)](ClO(4))(2) x 2 CH(2)Cl(2) x 2 H(2)O (7) (dark-red), are reported. The structural determinations have allowed insight into the structure-function relationships governing the observed color variation between these species.

Coordination modes between copper(II) and N-acetylneuraminic (sialic) acid from a 2D-simulation analysis of EPR spectra. Implications for copper mediation of sialoglycoconjugate chemistry relevant to human biology.

The equilibrium distribution of species formed between Cu(II) and N-acetylneuraminic (sialic) acid (I, LH) at 298 K has been determined using a two-dimensional (2D) simulation analysis of electron paramagnetic resonance (EPR) spectra. In acidic solutions (pH values < 4), the major species present are Cu(2+), [CuL]+ [logbeta = 1.64(4)], and [CuL2] [logbeta = 2.77(5)]. At intermediate pH values (4.0 < pH < 7.5), [CuL2H-1]- [logbeta = -2.72(7)] and two isomers of [CuLH-1] [logbeta (overall) = -3.37(2)] are present. At alkaline pH values (7.5 < pH < 11), the major species present is [CuL2H-2]2-, modeled as three isomers with unique giso and Aiso values [logbeta (overall) = -8.68(3)]. Two further species ([CuLH-3]2- and [CuL2H-3]3-) appear at pH values > 11. It is proposed that [CuL]+ most likely features I coordinated via the deprotonated carboxylic acid group (O1) and the endocyclic oxygen atom (OR) forming a five-membered chelate ring. Select Cu(II)-I species of the form [CuLH-1] may feature I acting as a dianionic tridentate chelate, via oxygen atoms derived from O1, OR, and one deprotonated hydroxy group (O7 or O8) from the glycerol tail. Alternatively, I may coordinate Cu(II) in a bidentate fashion as the tert-2-hydroxycarboxylato (O1,O2) dianion. Spectra predicted for Cu(II)-I complexes in which I is coordinated in either a O1,OR {I1-} or O1,O2 {I2-} bidentate fashion {e.g., [CuL]+ (O1,O R), [CuL2] (bis-O1,O R), [CuLH-1] (isomer: O1, O2), [CuL2H-1]- (O1, O R; O1, O2), and [CuL2H-2]2- (isomer: bis-O1, O2)} have "irregular" EPR spectra that are ascribed to the existence of Cu(II)-I(monomer) <==> Cu(II)-I(polymer) equilibria. The formation of polymeric Cu(II)-I species will be favored in these complexes because the glycerol-derived hydroxyl groups at the complex periphery (O, 7O, 8O9) are available for further Cu(II) binding. The presence of polymeric Cu(II)-I species is supported by EPR spectral data from solutions of Cu(II) and the homopolymer of I, colominic acid (Ipoly). Conversely, spectra predicted for Cu(II)-I complexes where I is coordinated in a {I2-} tridentate {e.g., [CuLH-1] (isomer: O1, O R, O7, or O8) and [CuL2H-2]2- (isomer: bis-O1,O R,O7, or O8)} or tetradentate fashion {I3-} {e.g., [CuLH-3]2- (O1, O R, O, 8O9)} are typical for mononuclear tetragonally elongated Cu(II) octahedra. In this latter series of complexes, the tendency toward the formation of polymeric Cu(II)-I analogues is small because the polydentate I effectively wraps up the mononuclear Cu(II) center. This work shows that Cu(II) could potentially mediate the chemistry of sialoglycoconjugate-containing proteins in human biology, such as the sialylated amyloid precursor protein of relevance to Alzheimer's disease.

Macrocyclic ligand design. Structure-function relationships involving the interaction of pyridinyl-containing, oxygen-nitrogen donor macrocycles with selected transition and post transition metal ions on progressive N-benzylation of their secondary amines.

Structure-function relationships underlying the interaction of progressively N-benzylated N(4)O(2)-donor macrocycles with cobalt(II), nickel(II), copper(II), zinc(II), cadmium(II), silver(I) and lead(II) have been probed using a range of techniques that include X-ray diffraction, DFT computations, solvent extraction, potentiometric stability constant determinations and competitive membrane transport experiments. Collectively, the results indicate that N-benzylation of the secondary amine donor groups of the parent macrocyclic ring results in an enhanced tendency towards selectivity for silver(I) relative to the other six metals investigated. The observed behaviour serves as additional exemplification of the previously proposed concept of selective 'detuning' as a mechanism for metal ion discrimination.

Metal ion recognition via 'selective detuning'. The interaction of selected transition and post-transition metal ions with a mono-N-benzylated O2N3-donor macrocycle and its xylyl-bridged ring analogue.

The interaction of cobalt(II), nickel(II), copper(II), zinc(II), cadmium(II), silver(I) and lead(II) with symmetrical mono-N-benzylated and xylyl-linked macrocyclic ligands derived from the O2N3-macrocycle, 1,12,15-triaza-3,4:9,10-dibenzo-5,8-dioxacycloheptadecane, has been investigated. The log K values for the respective 1 : 1 complexes in 95% methanol (I= 0.1; Et4NClO4, 25 degrees C) of the mono-benzylated derivative have been determined potentiometrically and the results compared with the values obtained previously for the parent (non-benzylated) ring system as well as for related di- and tri-benzylated macrocyclic species. Mono-benzylation results in slightly enhanced stability for the 1 : 1 silver(I) complex while the values for the corresponding complexes of the other six ions are in each case decreased even though the highest stability is still maintained for the 1 : 1 copper(II) complex. The log K results are in accord with a previous proposal that N-benzylation of amine-containing macrocyclic rings of the present type will normally have only a minor (positive or negative) influence on the affinity towards silver(I) while the corresponding binding strengths towards the remaining six metal ions are significantly reduced-behaviour we term 'selective detuning'. Competitive seven-metal transport experiments across a bulk chloroform membrane have been performed using both ligand systems as ionophores. In parallel to the log K results, transport selectivity for copper(II) was exhibited by both systems, with similar transport efficiencies being evident when compared on a 'per macrocyclic cavity' basis.