The Stability Of Tri-, Di-, And Monofluoro- Methyl/Methoxy/Methylthio Groups Under Acidic And Basic Conditions

Fluoro-containing group can modify the physico-chemical and metabolism properties of compounds, and they were widely used in medicinal chemistry and agricultural chemistry. Among them, the trifluoro-, difluoro-, monofluoromethyl/methoxy/ methylthio arene are very popular. Up to date, most research focuses on the introduction of fluoro-containing group into aryl ring, only few work has been reported on the stability of fluoro-containing group of arene ring. Sometimes, these fluoroaryl may experience acidic or alkali conditions during multi-step synthesis. Therefore, systemically study the stability of these fluorine-containing group under acidic and alkali conditions are important for their synthetic route design in medicinal chemistry.In this paper, the stability of different fluorine-containing fragments (CF3, OCF3, SCF3, CF2H, OCF2H, etc.) under acidic and basic conditions was studied systematically. And several factors were taken into consideration, including the strengths of acids and bases, the electronic effects of subsitituents and temperature. Based on the reaction phenomena and the structures of the products, the mechanisms of the reactions were proposed. Overall, the substrates demonstrated rough stability sequence as OCF3> SCF3? CF3>OCF2H?CF2H?SCF2H>OCH2F?CH2F?SCH2F. The stability is related to the number of fluorine atoms attached to carbon atom. The more fluorine attached, the more stable C-F bond is. The electronic effect of O atom also has an impact on the stability of those substrates, as the strong electronegativity of O can make C-F bond less polarizable and improve stability.Our research results lead to a better understanding of the properties of fluoro-moieties on aryl ring and provide guidance in the synthesis process to avoid the broken of fluorine-containing.