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.