Biomimetic Reductive Cleavage of Keto Aryl Ether Bonds by Small-Molecule Thiols

The nucleophilic and reductive properties of thiolates and thiols make them ideal candidates as redox mediators via the thiol/disulfide couple. One mechanism for biological lignin depolymerization entails reduction of keto aryl ether bonds by an S_N 2 mechanism with the thiol redox mediator glutathione. In this study, mimicking this chemistry in a simple protein- and metal-free process, several small organic thiols are surveyed for their ability to cleave aryl keto ethers that model the β-O-4 linkages found in partially oxidized lignin. In polar aprotic solvents, β-mercaptoethanol and dithiothreitol yielded up to 100 % formation of phenol and acetophenone products from 2-phenoxyacetophenone, but not from its reduced alcohol congener. The effects of reaction conditions and of substituents on the aryl rings and the keto ether linkage are assessed. These results, together with activation barriers computed by quantum chemical simulations and direct observation of the expected intermediate thioether, point to an S_N 2 mechanism. This study confirms that small organic thiols can reductively break down lignin-relevant keto aryl ether linkages.