Insight into the methylene C–H bond cleavage of ethylbenzene during ethylbenzene hydroxylation using EBDH as a catalyst, a DFT study

Abstract

The hydroxylation of ethylbenzene to ( S)-1-phenylethanol with the help of ethylbenzene dehydrogenase (EBDH) is a stereospecific catalytic reaction. This hydroxylation process involves the C–H bond cleavage of methylene part of ethylbenzene and transfer of its hydrogen to the oxygen atom attached with the metal at the active site of EBDH as a first step, which leads to the formation of an intermediate. The second step involves the transfer of OH from the active-site metal back to the carbon of intermediate, resulting in the formation of ( S)-1-phenylethanol. This C–H bond cleavage could be homolytic or heterolytic and directly affect the reaction mechanism of ethylbenzene hydroxylation. In this article, density functional theory studies were performed on the ethylbenzene-bound EBDH active-site model complexes to investigate the impact of the C–H bond cleavage of methylene part of ethylbenzene on the reaction mechanism of ethylbenzene hydroxylation. For this, different protonation states and participation of amino acid residues near the Mo center of EBDH were considered. Models with protonation of His192, Lys450, and Asp223 and model without protonation were investigated for comparison. Computed relative energies indicate that the overall lowest energy barrier pathway results when ionic (heterolytic) and radical (homolytic) pathways are combined.