Enhanced selectivity for Mg2+ with a phosphinate-based chelate: APDAP versus APTRA

Abstract

o-Aminophenol-N,N,O-triacetate, known as APTRA, is one of the most well-established ligands for targeting magnesium ions but, like other aminocarboxylate ligands, it binds Ca²⁺ much more strongly than Mg²⁺. The synthesis of an O-phosphinate analogue of APTRA is reported here, namely o-aminophenol-N,N-diacetate-O-methylene-methylphosphinate, referred to as APDAP. Metal binding studies monitored using UV-visible spectroscopy show that the affinity of APDAP for Ca²⁺ is reduced by over two orders of magnitude compared to APTRA, and for Zn²⁺ by over three orders of magnitude, whereas the affinity for Mg²⁺ is attenuated to a much lesser extent, by a factor of only about 7. The selectivity towards Mg²⁺ is thus substantially improved. DFT calculations support the notion that longer P–O and P–C bonds in APDAP (compared to corresponding C–O and C–C bonds in APTRA) favour a larger angle at the metal, an effect that is less unfavourable for smaller ions like Mg²⁺ than for larger ions such as Ca²⁺. Derivatives of APDAP can be anticipated that will offer improved sensing of Mg²⁺ in the presence of Ca²⁺, in the physiologically important millimolar concentration range.