Application of natural deep eutectic solvents in the continuous process for synthesis of resveratrol analogues by the Wittig reaction

Abstract

In recent years, resveratrol and its analogues have gained significant attention due to their potential bioactivity in disease prevention and therapy. Consequently, there is a growing interest in producing these compounds in larger quantities, which increases the importance of chemical synthesis methods. The Wittig reaction is commonly used for the synthesis of these stilbene analogues and can be carried out in a two-phase system using phase-transfer catalysis (PTC). This approach helps to avoid the use of harsh and hazardous bases. In addition, hazardous solvents such as dichloromethane (DCM) are replaced by natural deep eutectic solvents (NADESs), which increases the safety and sustainability of the synthesis. Further improvements in the productivity of the process can be achieved through flow chemistry, which offers safer and less time-consuming production compared to batch processes. In this study, resveratrol analogues were synthetized using two approaches. In the first approach, the reaction was carried out in DCM, and in the second, DCM was replaced by synthetized hydrophobic NADESs to make the process more environmentally friendly. The preliminary results, obtained in a batch reactor, indicated that DCM could be replaced with NADES as a solvent for resveratrol analogues synthesis. To intensify the process, an integrated Wittig-PTC reaction and product separation were performed in a millireactor and two different microseparators (liquid-liquid membrane microseparator Zaiput SEP-10 and 3D printed membrane-free liquid–liquid microseparator) connected in series. In order to enhance conversion and productivity, different process parameters (temperature, residence time, millireactor diameter, and pressure) were tested. After determining the best process conditions, the product-rich DCM/NADES phase was separated using a microseparator. The best conditions for reaction performed in a millireactor using DCM as solvent were a temperature of 40–45 °C, a residence time of 20 min, a millireactor diameter of 1.016 mm, and a pressure of 8 bar where a selectivity of 28.12%, calculated on the trans-isomer, was achieved. By combining the millireactor and the Zaiput microseparator, a complete product-rich DCM phase was separated from the aqueous phase. When DCM was replaced by NADES, a temperature of 40–45 °C and a residence time of 10 min were selected as optimal, resulting in a selectivity of 27.30%. When the millireactor was combined with a 3D printed membrane-free liquid–liquid microseparator, the product-rich NADES phase was separated from the aqueous phase with minor loses.