Amino Acid Ester based Phenolic Ionic Liquids as a Potential Solvent for the Bioactive Compound Luteolin: Synthesis, Characterization, and Food Preservation Activity

Abstract Ionic liquids (ILs) have gained great attention as potent solubilizing agents of poorly soluble bioactive compounds. The use of Luteolin (LUT) – a natural bioactive compound – is limited because of its poor aqueous solubility. To address this issue, this study reports potential ionic liquids (ILs) for effectively solubilizing LUT at ambient temperature. First, promising ILs were screened from a potential 180 ILs that were proposed by the combination of 20 standard amino acid ethyl esters cations and nine phenolic acids anions using the conductor-like screening model for real solvents (COSMO-RS); the activity coefficients of LUT at infinite dilution in ILs were used as the screening criteria. Four proline ethyl ester phenolate ILs (PEEP-ILs) composed of a biocompatible proline ethyl ester and bioactive phenolic acids (trans-ferulic, vanillic, p-coumaric, and 4-hydroxybenzoic acid) were selected and synthesized. The synthesized PEEP-ILs were characterized through 1H NMR, FT-IR, elemental analysis, TGA, and DSC. The experimental solubility of LUT in PEEP-ILs (60% IL in water) showed excellent solubility. Among the PEEP-ILs, proline ethyl ester ferulate (IL[ProEt][Fer]) exhibited the best LUT solubility, followed by ILs with p-coumarate (IL[ProEt][Cou]), vanillate (IL[ProEt][Van]), and 4-hydroxybenzoate (IL[ProEt][Ben]). 1H NMR assessment and COSMO-RS prediction confirmed that the ILs facilitated the solubilization of LUT through multiple hydrogen bonding, π−π, and cation−π interactions between the LUT and the ILs. The biocompatibility study revealed that PEEP-ILs were relatively harmless and low toxicity compared with conventional imidazolium, pyridinium, pyrrolidinium, piperidinium, and morpholinium-based ILs. The LUT dissolved in the newly-synthesized PEEP-ILs and demonstrated better organoleptic properties on red apple slices. These results indicate that PEEP-ILs can be potential green alternatives to conventional toxic solvents for dissolving poorly water-soluble bioactive natural preservatives.