Revisiting the Algar-Flynn-Oyamada (AFO) Reaction Mechanism: Computational and other Studies

The flavonoid family is a diverse family of natural phenolic compounds, with multiple biological properties. Both flavonols and aurones and their derivatives are key flavonoid compounds. These molecules traditionally have been obtained through the classical Algar, Flynn and Oyamada (AFO) reaction by treatment of 2’-hydroxychalcones with alkaline hydrogen peroxide. The mechanism is controversial, with indications of the formation of an epoxide intermediate when there is a substituent in the 6’-position (giving aurones and other benzofuran-2-one derivatives), and in the case of the 6’-substituted substratesan oxidative cyclization (directly or step-wise) involving no epoxide intermediates to give flavanols (Dean and Podimuang mechanism). In this paper, the mechanism of this reaction was studied computationally (DFT calculations) and the results indicated that for the unsubstituted systems the Dean and Podimuang mechanism is favoured both kinetically and thermodynamically, but in the case of the substituted systems, although the former mechanism is again favoured kinetically, both mechanisms show similar energies at the thermodynamic level, indicating that both the Dean and Podimuang mechanism and the epoxide forming pathway may operate in parallel. Interestingly, the calculations indicated an unexpected electrophilic hydroperoxide epoxidation route instead of a nucleophilic epoxidation route. Modified AFO conditions were studied whereby H2O2 was replaced by mCPBA, these experiments afforded mainly flavanone and some AFO products in low yields.