Theoretical study on the influence of OH group position on the free radical scavenging ability of tryptamine derivatives

Abstract

A density functional theory (DFT) study investigated the influence of hydroxyl (OH) groups on the free radical scavenging capacity of tryptamine derivatives (OH-TAs). Stable forms of OH-TAs were evaluated in both gaseous and aqueous environments. While neutral forms predominate in the gas phase, cationic forms (protonated at the NH₂ group) are favored in aqueous solution. Frontier molecular orbital (FMO) and molecular electrostatic potential (MEP) analyses identified active sites. Electron-donating regions are primarily located on the benzene and pyrrole rings, whereas electron-accepting areas are concentrated on the OH and NH groups. In water, the lowest unoccupied molecular orbitals (LUMOs) of OH-TAs shift and localize on the NH₃⁺ group. Calculated global reactivity descriptors indicate that 9-OH-TA exhibits the highest free radical scavenging efficiency. Molecular electrostatic potential (MEP) analysis further reveals that the hydrogen atoms in the –OH groups of the OH-TAs are the most favorable sites for nucleophilic attacks. Thermodynamic parameters, including bond dissociation energy (BDE), ionization potential (IP), and proton affinity (PA), were calculated to assess antioxidant properties. Reaction mechanism analyses reveal that hydrogen atom transfer (HAT) is the preferred pathway in the gas phase, while the single electron transfer (SET) mechanism dominates in aqueous solutions at physiological pH (7.4). Among the studied derivatives, 9-OH-TA demonstrates the highest efficiency in scavenging HOO˙ radicals, with total rate constants of 1.9 × 10⁷ M⁻¹ s⁻¹ in the gas phase and 5.2 × 10⁷ M⁻¹ s⁻¹ in water.