The chemistry of the enzyme glutathione peroxidase and synthetic organoselenium enzyme mimics has been a significant research interest for more than three decades. In this work, the results of a computational study employing modern electronic structure methods to model the reactions of a synthetic glutathione peroxidase mimic are presented. The ability of nine density-functional theory methods and thirteen basis sets to predict both molecular geometries and bond dissociation energies in organoselenium compounds is examined. This is used to determine the best methodology to employ for the study of glutathione peroxidase mimics. The key reactions in the catalytic mechanism of the organoselenium antioxidant N,N-dimethyl-benzylamine-2-selenol are the focus of the remainder of the document. This is a three-step mechanism which includes many of the organic forms adopted by selenium compounds, including selenol, oxoacids, and selenylsulfides. In the first step of the cycle, the well-studied reduction of hydrogen peroxide by a selenol and a diselenide is modelled. The second step modelled is a substitution reaction at the selenium centre of a selenenic acid with a thiol. The final step discussed is the reduction of the selenium centre in a selenylsulfide, regenerating the selenol and forming a disulfide species. Each mechanism is evaluated by discussing both molecular geometries and reaction energetics. To close the document, the peroxide reduction reaction is revisited to determine the effects of substitution on the phenyl ring of the synthetic antioxidant. This serves as a preliminary attempt to improve the antioxidant efficiency of this compound. In addition to a discussion of the changes in reaction energetics predicted, the topology of the electron density is studied using the quantum theory of atoms in molecules to better understand how the distribution of electron density is affected by substituents.

This thesis is concerned with the synthesis and evaluation of regenerable chalcogen containing antioxidants. Variously substituted 2,3-dihydrobenzo[b]selenophene-5-ol antioxidants were evaluated in order to gain information about structure/reactivity-relationships. Within the series explored, the most regenerable unsubstituted compound inhibited lipid peroxidation for more than 320 minutes when assayed in a two-phase lipid peroxidation model in the presence of N-acetylcysteine (NAC). α-Tocopherol which could inhibit lipid peroxidation for 90 minutes under similar conditions was therefore easily outperformed. The antioxidant activity of the parent was also documented in an aqueous environment. The best catalyst quenched/inhibited ROS production by neutrophils and PMA-stimulated macrophages more efficiently than Trolox. In addition, over a period of seven days, no disruption in proliferation for the cell lines used was observed when exposed to our synthetic compound or Trolox at a concentration of 60 µM. 3-Pyridinols substituted with alkyltelluro groups in the ortho-position were more regenerable in the two-phase model than their corresponding para-substituted analogues in the presence of NAC and also inhibited autoxidation of styrene in a catalytic fashion in homogenous phase in the presence of N-tert-butoxycarbonyl cysteine methyl ester (LipCys), a lipid-soluble analogue of NAC. The best inhibitors quenched peroxyl radicals more efficiently than α-tocopherol. They could also catalyze reduction of organic hydroperoxides in the presence of thiols and therefore mimic the action of the glutathione peroxidase enzymes. Mechanisms for the catalysis are proposed. Octylthio, octylseleno and octyltelluro analogues of butylated hydroxyanisole (BHA) were synthesized and evaluated. Among these, the tellurium compound was superior to α-tocopherol in the presence of NAC both when it comes to quenching capacity and regenerability.  Organochalcogen substituent effects in phenolic compounds were studied by using EPR, IR and computational methods.