Fluorine chemistry has taken a pivotal role in chemical reaction discovery, drug development, and chemical biology. NMR spectroscopy, arguably the most important technique for the characterization of fluorinated compounds, is rife with highly inconsistent referencing of fluorine NMR chemical shifts, producing deviations larger than 1 ppm. Herein, we provide unprecedented evidence that both spectrometer design and the current unified scale system underpinning the calibration of heteronuclear NMR spectra have unintentionally led to widespread variation in the standardization of F NMR spectral data. We demonstrate that internal referencing provides the most robust, practical, and reproducible method whereby chemical shifts can be consistently measured and confirmed between institutions to less than 30 ppb deviation. Finally, we provide a comprehensive table of appropriately calibrated chemical shifts of reference compounds that will serve to calibrate F spectra correctly.

In this Review, we highlight recent advances in the understanding and design of N‐functionalized pyridinium scaffolds as redox‐active, single‐electron, functional group transfer reagents. We provide a selection of representative methods that demonstrate reactivity and fundamental advances in this emerging field. The reactivity of these reagents can be divided into two divergent pathways: homolytic fragmentation to liberate the N‐bound substituent as the corresponding radical or an alternative heterolytic fragmentation that liberates an N‐centered pyridinium radical. A short description of the elementary steps involved in fragmentation induced by single‐electron transfer is also critically discussed to guide readers towards fundamental processes thought to occur under these conditions.

As imple trifluoromethoxylation method enables non-directed functionalization of CÀHb onds on ar ange of substrates,providing access to aryl trifluoromethyl ethers.This light-driven process is distinctly different from conventional procedures and occurs through an OCF 3 radical mechanism mediated by ap hotoredoxc atalyst, whicht riggers an N À O bond fragmentation. The pyridinium-based trifluoromethoxylation reagent is bench-stable and provides access to synthetic diversity in lead compounds in an operationally simple manner.Scheme 1. Advances in late-stage arene trifluoromethoxylation.

Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents.T he resulting C(sp 2 )ÀHf unctionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds.M echanistic studies that include the first spectroscopic evidence of as pin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N À Xp yridinium reagents mediated by visible light.

The reaction of nucleophilic tertiary amines with trifluoromethyl and pentafluoroethyl methyl ethers provides quaternary ammonium trifluoromethoxide (NR4OCF3) and pentafluoroethoxide (NR4OCF2CF3) salts, respectively, in good yields. The new trifluoromethoxide salts disclosed herein are uniquely stable for extended periods of time in both the solid state and in solution, which complements contemporary reagents. Here we describe the preparation of a range of NR4OCF3 salts, their long-term stability, and utility in substitution reactions.

We leverage the slow liberation of nitrogen dioxide from a newly discovered, inexpensive succinimide‐derived reagent to allow for the C−H diversification of alkenes and alkynes. Beyond furnishing a library of aryl β‐nitroalkenes, this reagent provides unparalleled access to β‐nitrohydrins and β‐nitroethers. Detailed mechanistic studies strongly suggest that a mesolytic N−N bond fragmentation liberates a nitryl radical. Using in situ photo‐sensitized, electron paramagnetic resonance spectroscopy, we observed direct evidence of a nitryl radical in solution by nitrone spin‐trapping. To further exhibit versatility of N‐nitrosuccinimide under photoredox conditions, the late‐stage diversification of an extensive number of C−H partners to prepare isoxazolines and isoxazoles is presented. This approach allows for the formation of an in situ nitrile oxide from a ketone partner, the presence of which is detected by the formation of the corresponding furoxan when conducted in the absence of a dipolarophile. This 1,3‐dipolar cycloaddition with nitrile oxides and alkenes or alkynes proceeds in a single‐operational step using a mild, regioselective, and general protocol with broad chemoselectivity.

The first light-driven method for the α-trifluoromethoxylation of ketones is reported. Enol carbonates react with N -trifluoromethoxy-4-cyano-pyridinium, using the photoredox catalyst 4-CzIPN under 456 nm irradiation, affording the α-trifluoromethoxy ketones in ≤50% isolated yield and complete chemoselectivity. As shown by 29 examples, the reaction is general and proceeds very rapidly under batch (1 h) and flow conditions (2 min). Diverse product manipulations demonstrate the synthetic potential of the disclosed method in accessing elusive trifluoromethoxylated bioactive ingredients.

Eine einfache Methode fürd ie Trifluormethoxylierung nichtfunktionalisierter C-H-Bindungen bietet Zugang zu aromatischen Trifluoromethylethern. Die lichtgetriebene Reaktion unterscheidet sich von herkçmmlichen Prozessen, indem das OCF 3 -Radikal durch eine photoredoxkatalytische N-O-Bindungsfragmentierung generiert wird. Das entsprechende Pyridinium-basierte Reagenz ist stabil und ermçglicht einen einfachen Zugang zu verschiedenen Verbindungen der oben genannten Klasse.