Synthesis of novel N-alkyl caffeic acid amides with the enhanced interfacial activity and antioxidant activity using rational molecular design

The antioxidant activity of hydrophilic caffeic acid (CA) in oil-containing systems is often limited by its insufficient accumulation at the oil–water interface. To address this issue, the N-alkyl CA amides were synthesized by modifying CA with different alkyl chains and tryptophan ethyl ester to improve interfacial activity and antioxidant performance. The N-alkyl CA amides derivatives were evaluated by interfacial tension analysis, oil-in-water (O/W) emulsion oxidation tests, and density functional theory (DFT) calculations. The results showed that the lipophilicity and interfacial activity of CA amides were significantly increased by N-alkylation, and all N-alkyl CA amides derivatives showed the stronger radical-scavenging activity than CA. Furthermore, lipid oxidation in both linoleic acid (LA) and O/W emulsions was effectively inhibited by medium- (octyl) and long-chain (dodecyl) derivatives. The addition of N-octyl CA amide notably increased the oxidation induction temperature of LA from 119.05 °C to 151.84 °C. The formation of lipid oxidation products in the emulsions with N-dodecyl CA amide was significantly inhibited. DFT results further confirmed that the intrinsic antioxidant reactivity of CA amides was enhanced by tryptophan conjugation, whereas the interfacial activity was regulated by the alkyl-chain length. This study demonstrated that this rational molecular design provided an effective strategy for developing novel and highly efficient antioxidants for oil-based food applications.