Dimerisation process of silybin-type flavonolignans: insights from theory

Area of Science:

• Computational Chemistry
• Natural Product Chemistry
• Physical Chemistry

Background:

• Natural polyphenols possess antioxidant properties, partly due to oxidation by free radicals.
• Polyphenol oxidation can lead to the synthesis of new biologically relevant compounds, such as dimers.
• Silybin and dehydrosilybin, from milk thistle (Silybum marianum), are known to form dimers.

Purpose of the Study:

• To theoretically investigate the regioselective dimerisation of silybin and dehydrosilybin.
• To elucidate the physicochemical mechanisms governing polyphenol dimerisation using computational methods.
• To explain the observed regioselectivity in the formation of polyphenol dimers.

Main Methods:

• Density Functional Theory (DFT) calculations were employed to model the dimerisation process.
• Thermodynamic and kinetic parameters were computed to analyze the reaction pathways.
• Analysis focused on hydrogen atom transfer, bond formation, and tautomerisation steps.

Main Results:

• Dimerisation proceeds via a two-step mechanism: initial bond formation followed by tautomerisation.
• Bond formation is the rate-limiting step in the dimerisation process.
• Tautomerisation is crucial for thermodynamic favourability (ΔG<0); its absence limits dimerisation feasibility, explaining regioselectivity.

Conclusions:

• The study provides a theoretical framework explaining the regioselective dimerisation of natural polyphenols like silybin.
• The feasibility and regioselectivity of polyphenol dimerisation are dictated by the ability of the intermediate to undergo tautomerisation.
• Understanding these mechanisms can aid in the synthesis of novel biologically active polyphenol derivatives.