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

Abstract

The protonation equilibria of a pentadentate ligand, N, N′-(2,2′-azanediylbis(ethane-2,1-diyl))dipicolinamide ([H 2(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[H 2(5555)-N]H species at low pH, while amide group deprotonation at higher pH resulted in the formation of Cu[H 2(5555)-N]H −1 and Cu[H 2(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)–[H 2(5555)-N] system indicated that although the Cu[H 2(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.