Phenolic Schiff bases are known for their diverse biological activities and ability to scavenge free radicals. To elucidate (1) the structure-antioxidant activity relationship of a series of thirty synthetic derivatives of 2-methoxybezohydrazide phenolic Schiff bases and (2) to determine the major mechanism involved in free radical scavenging, we used density functional theory calculations (B3P86/6-31+(d,p)) within polarizable continuum model. The results showed the importance of the bond dissociation enthalpies (BDEs) related to the first and second (BDEd) hydrogen atom transfer (intrinsic parameters) for rationalizing the antioxidant activity. In addition to the number of OH groups, the presence of a bromine substituent plays an interesting role in modulating the antioxidant activity. Theoretical thermodynamic and kinetic studies demonstrated that the free radical scavenging by these Schiff bases mainly proceeds through proton-coupled electron transfer rather than sequential proton loss electron transfer, the latter mechanism being only feasible at relatively high pH.

Natural and synthetic Schiff bases are known for their diverse biological activies and potent antioxidant and free radical scavenging activity. A series of 31 Schiff bases (e.g. 2) were synthetized through the condensation of 2-methoxybenzohydrazide (1) and different aldehydes in methanol. The antioxidant activities of these Schiff bases were evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test. To rationalize their structure-antioxidant activity relationship, density functional theory (DFT) calculations have been performed at B3P86/6-31+G(d,p) level in gas phase and in solvent using a polarizable continum model (PCM). Both experimental and DFT results emphasize the importance of the (i) catechol moiety, (ii) number of OH groups, (iii) delocalization of spin density (such as in 3), and (iv) bond dissociation enthalpies (BDE for a first hydrogen atom transfer and BDE d for a second hydrogen atom transfer) in the antioxidant activity of that series of Schiff bases. Thermodynamic and kinetic studies of the reactivty of Schiff bases with free radicals (e.g. DPPH and •OOCH 3 ) have shown that the coupled proton electron transfer (CP-ET) is the major mechansim to scavenge free radicals due to low free activation barriers as compared to the electron transfer proton transfer (ET-PT) mechanism.