Ionic liquid cytotoxicity in mouse macrophage J774.1 cells: Effects of alkyl chain length, cation core, and anion type

Ionic liquids (ILs) are salts with melting points below 100°C. These materials are promising novel solvents in organic reactions, as new electrolytes, and in protein stabilization, able to refold enzymes and aid in drug discovery. IL properties are strongly influenced by the types of their constituent cations and anions. To date, many ILs with unique solvent properties not found in water or organic solvents are reported. However, IL toxicity evaluations often focus on trends associated with widely used imidazolium cations. Consequently, knowledge regarding the toxicity of individual ionic structures and their combinations is limited. This study investigated alkylphosphonium and alkylammonium cation derivatives, evaluating their cytotoxicity against mouse macrophage J774.1 cells using dihydrogen phosphate ([dhp]) or bromide (Br) ions as anions. Experiments were conducted using alkylphosphonium cation derivatives ((C₄H₉)₃RP⁺, [P444R]) with varying alkyl chain lengths (R: 4; C₄H₉, 8; C₈H₁₇, and 12; C₁₂H₂₅) and on tetrabutylammonium cation derivatives [N4444]. This study revealed that [P44412][dhp] yielded the highest toxicity, which decreased with shorter alkyl chains. A similar trend was observed with Br as the anion. For [P444R], anion variation did not significantly affect toxicity. Comparing [P4444][dhp] and [N4444][dhp], the phosphonium cation showed lower ED₅₀ values, indicating higher toxicity. This tendency persisted when Br was used as the anionic species. In summary, for the ILs evaluated, the quaternary cationic species of the IL effects the greatest influence on IL toxicity.