The Reactivity of Diiron(I) Bis-cyclopentadienyl Tricarbonyl Aminocarbyne Complexes in Aqueous Media: A Case Study for Iron-Based Anticancer Agents

The biological effects of diiron(I) aminocarbyne complexes [Fe2Cp2(CO)(L)(μ-CO){μ-CNR(R')}]+ originate from their intracellular disassembly, releasing reactive iron species. Herein, a systematic multitechnique investigation of the reactivity of tricarbonyl (L = CO) complexes in aqueous media was carried out. Well-soluble nitrate salts were prepared on a (multi)gram scale and characterized by IR, NMR, and XRD. The degradation process in water or DMEM was assessed after 72 h at 37 °C over a wide concentration range via 1H NMR and UV-vis. Results were integrated by pH, conductivity, UV-vis and 1H NMR measurements at 24 h intervals and ICP-OES. The process follows zero-order kinetics above mM concentration, with partial formation of the corresponding secondary amine (RR'NH) and cyclopentadiene. The slowly forming brown precipitates contain iron(III)-oxy(hydroxides) and minor organic/organometallic components as shown by CHNS analyses, IR, Raman and ESI-MS. Evaluating the effects of O2, ambient light, temperature, pH, Me3NO on the process via 1H NMR and UV-vis provided key mechanistic insights. Addition of 1,3,5-triaza-7-phosphadamantane (PTA) enabled trapping of the CO-substituted intermediate [Fe2Cp2(CO)(PTA)(μ-CO){μ-CNR(R')}]+. The pathway leading to total disruption of the coordination sphere was elucidated by DFT. Overall, these results lay the foundations for understanding the behavior of this promising class of anticancer metallodrugs in physiological settings.