The antioxidant activity of ortho- and meta-substituted tryptophan derivatives has been investigated in the gas phase and water. The reaction enthalpies of antioxidant activity of studied derivatives have been calculated and compared with corresponding values of tryptophan. Results show that EWG substituents increase the BDE, IP, and ETE while EDG appendages cause a rise in the PA and PDE. The tryptophan derivatives with lowest BDE, IP, and PA values were identified as the compounds with high antioxidant activity. Results show that the substituents in ortho-position have high potential for synthesis of novel tryptophan derivatives. Results show that EDG-substituted tryptophans can process their protective role via HAT mechanism in gas phase. On the other hand, SPLET mechanism represents the thermodynamically favored process for EWG-substituted tryptophans in water. The calculated reaction enthalpies of the substituted tryptophans have linear dependences with Hammett constants and EHOMO that can be utilized in the selection of suitable substituents for the synthesis novel antioxidants based on tryptophan
