Solution equilibria of copper(II) complexation with N,N′-(2,2′-azanediylbis(ethane-2,1-diyl))dipicolinamide: A bio-distribution and dermal absorption study

The protonation equilibria of a pentadentate ligand, N,N′-(2,2′-azanediylbis(ethane-2,1-diyl))dipicolinamide ([H2(5555)-N]) and the complexation of this ligand with Cu(II) Ca(II), Zn(II) and Ni(II) have been studied by pH-potentiometry, 1H NMR spectroscopy and UV-vis spectrophotometry. 1H NMR detected the protonation of the pyridyl groups and formation of Cu[H2(5555)-N]H species at low pH, while amide group deprotonation at higher pH resulted in the formation of Cu[H2(5555)-N]H−1 and Cu[H2(5555)-N]H−2 species in solution. Potentiometric detection of protonated species was limited by the acidic nature of the pyridyl nitrogen donors. From UV-vis spectroscopy it is suggested that the amide nitrogens are coordinated. This conclusion is supported by Molecular Mechanics calculations. Water-octanol partition coefficients for the Cu(II)-[H2(5555)-N] system indicated that although the Cu[H2(5555)-N]H−1 species is largely hydrophilic, approximately 54% of the complex goes into the organic phase. This percentage is able to promote dermal absorption of copper with a calculated penetration rate of 1.92 × 10−1 cm h−1. This was confirmed by dermal absorption studies which illustrate the role of hydrophobicity in promoting percutaneous drug administration.