Substituent Effects on the Direct Photolysis of Benzotrifluoride Derivatives

Abstract

The chemical class of benzotrifluoride derivatives is widely used in active ingredients of various commercial products, such as pharmaceuticals, pesticides, herbicides, and crop protection agents. Past studies have shown that some benzotrifluorides are not stable under UV irradiation in water and convert into benzoic acids due to C–F bond hydrolysis. It was also observed, but never systematically studied, that the ring substituents play an important role on the direct photochemical reactivity of the CF3 moiety. In the present work, we explore the structure–reactivity relationship between ring substituent and direct photodefluorination for 16 different substituents, by determining fluoride production rates, quantum yields, and half-lives, and found that strong electron-donating groups enhance the reactivity toward hydrolysis. In addition, flufenamic acid, travoprost, dutasteride, cyflumetofen, flutoanil, and teriflunomide were also examined, finding that their direct photochemical reactivity could be qualitatively predicted based on their ring substituents. We provide here a tool to evaluate the environmental persistence of benzotrifluoride contaminants, as well as to design more photodegradable new active ingredients.

Tracking Fluorine during Aqueous Photolysis and Advanced UV Treatment of Fluorinated Phenols and Pharmaceuticals Using a Combined 19F-NMR, Chromatography, and Mass Spectrometry Approach

“…Identification of fluorinated reaction products from photolysis processes has only received limited attention. − Thus, fluorinated products formed via degradation of these compounds may pose unforeseen consequences such as production of benzoic acids via the photolysis of trifluoro­methylphenyl dervatives . To better understand the degradation pathways of these fluorinated compounds in the environment, reliable detection methods must first be established.…”

Prioritizing Direct Photolysis Products Predicted by the Chemical Transformation Simulator: Relative Reasoning and Absolute Ranking

“…Manfrin et al (2020) studied how the substituents on the benzene ring could change the rates of direct photodefluorination for benzotrifluorides, which can be considered a SAR study for our purpose. 14 This transformation is described by the "trifluoromethyl photohydrolysis" reaction scheme in our reaction library. This study found that monosubstituted benzotrifluorides bearing an electron-donating group such as −OH, −NHMe, and −NH 2 on the ring enhanced photohydrolysis, while the ones bearing an electronwithdrawing group show lower photoactivity for the compounds they investigated.…”

“…Below, we provide a back-of-the-envelope example of how (Q)­SAR development could help improve the reaction library. Manfrin et al (2020) studied how the substituents on the benzene ring could change the rates of direct photodefluorination for benzotrifluorides, which can be considered a SAR study for our purpose . This transformation is described by the “trifluoromethyl photohydrolysis” reaction scheme in our reaction library.…”

Microwell Fluoride Screen for Chemical, Enzymatic, and Cellular Reactions Reveals Latent Microbial Defluorination Capacity for −CF 3 Groups

“…While oxidative defluorination has been demonstrated previously ( 29 , 73 , 74 ), the mechanism of defluorination of 4-fluorobenzotrifluoride was not immediately obvious. Moreover, the trifluoromethylphenyl moiety has become common in drugs and agricultural chemicals, with the goal of increasing effective lifetime by inhibiting microbial degradation ( 9 , 75 ). 4-Fluorobenzotrifluoride underwent only partial transformation via the toluene biodegradative (Tod) pathway, and this was the key to the large extent of defluorination observed.…”