New 19F NMR methodology reveals structures of molecules in complex mixtures of fluorinated compounds.

Alan J R Smith,Dušan Uhrín,Richard York,Nicholle G A Bell

doi:10.1039/d1sc06057k

Abstract

Although the number of natural fluorinated compounds is very small, fluorinated pharmaceuticals and agrochemicals are numerous. 19F NMR spectroscopy has a great potential for the structure elucidation of fluorinated organic molecules, starting with their production by chemical or chemoenzymatic reactions, through monitoring their structural integrity, to their biotic and abiotic transformation and ultimate degradation in the environment. Additionally, choosing to incorporate 19F into any organic molecule opens a convenient route to study reaction mechanisms and kinetics. Addressing limitations of the existing 19F NMR techniques, we have developed methodology that uses 19F as a powerful spectroscopic spy to study mixtures of fluorinated molecules. The proposed 19F-centred NMR analysis utilises the substantial resolution and sensitivity of 19F to obtain a large number of NMR parameters, which enable structure determination of fluorinated compounds without the need for their separation or the use of standards. Here we illustrate the 19F-centred structure determination process and demonstrate its power by successfully elucidating the structures of chloramination disinfectant by-products of a single mono-fluorinated phenolic compound, which would have been impossible otherwise. This novel NMR approach for the structure elucidation of molecules in complex mixtures represents a major contribution towards the analysis of chemical and biological processes involving fluorinated compounds.

Highlights

IntroductionAbout 20% of the commercial pharmaceuticals contain fluorine and the proportion of newly approved fluoropharmaceuticals is rising steadily.[2,3,4] fluoroagrochemicals have become indispensable[5] for crop production and protecting public health from parasitically transmitted infectious diseases; 53% of all active agrochemicals registered during 1998–2020 are classed as fluoro-agrochemicals.[6] New fragrance and semiochemical molecules can benefit from fluorination.[7] In addition, 18F is the most frequently used radioisotope in positron emission tomography radiopharmaceuticals in both clinical and preclinical research, and the search for simple and efficient 18F-labeling procedures is an active research area.[8]
While fluorine-containing compounds are the least abundant natural organohalides,[1] modern society has become dependent on numerous man-made fluorinated organic molecules such as pharmaceuticals and agrochemicals
By analysing a complex mixture of disinfection by-products (DBPs) produced by chloramination of a single fluorine-tagged molecule, we have demonstrated the feasibility of 19F-centred NMR structure determination of small molecules without the need for compound separation

Summary

Introduction

About 20% of the commercial pharmaceuticals contain fluorine and the proportion of newly approved fluoropharmaceuticals is rising steadily.[2,3,4] fluoroagrochemicals have become indispensable[5] for crop production and protecting public health from parasitically transmitted infectious diseases; 53% of all active agrochemicals registered during 1998–2020 are classed as fluoro-agrochemicals.[6] New fragrance and semiochemical molecules can benefit from fluorination.[7] In addition, 18F is the most frequently used radioisotope in positron emission tomography radiopharmaceuticals in both clinical and preclinical research, and the search for simple and efficient 18F-labeling procedures is an active research area.[8]. There is a need to characterise fluorinated molecules using efficient analytical methods, amongst which 19F

Methods

Results

Conclusion