Preface Recent advances in catalysis have made the incorporation of fluorine into complex organic molecules easier than ever before, but selective, general, and practical fluorination reactions remain sought after. Fluorination of molecules often imparts desirable properties such as metabolic and thermal stability, and fluorinated molecules are therefore frequently used as pharmaceuticals or materials. Even with the latest advances in chemistry, carbon–fluorine bond formation in complex molecules is still a significant challenge. Within the last few years, new reactions to make organofluorides have emerged and exemplify how to overcome some of the intricate challenges associated with fluorination.

A palladium compound facilitates rapid incorporation of radioactive fluoride into prospective tracers for medical imaging.

Using a system that accelerates the serendipitous discovery of new reactions by evaluating hundreds of DNA-encoded substrate combinations in a single experiment, we explored a broad range of reaction conditions for new bond-forming reactions. We discovered reactivity that led to a biomolecule-compatible, Ru(II)-catalyzed, visible light-induced azide reduction reaction. In contrast with current azide reduction methods, this reaction is highly chemoselective and is compatible with alcohols, phenols, acids, alkenes, alkynes, aldehydes, alkyl halides, alkyl mesylates, and disulfides. The remarkable functional group compatibility and mild conditions of this reaction enabled azide reduction to be performed on nucleic acid and oligosaccharide substrates without the detectable occurrence of side reactions. The reaction was also performed in the presence of a protein enzyme without loss of enzymatic activity, in contrast with two commonly used azide reduction methods. The visible light dependence of this reaction provides a means of photouncaging functional groups such as amines and carboxylates on biological macromolecules without using UV irradiation.

New chemistry methods for the synthesis of radiolabeled small molecules have the potential to impact clinical positron emission tomography (PET) imaging, if they can be successfully translated. However, progression of modern reactions from the stage of synthetic chemistry development to the preparation of radiotracer doses ready for use in human PET imaging is challenging and rare. Here we describe the process of and the successful translation of a modern palladium-mediated fluorination reaction to non-human primate (NHP) baboon PET imaging–an important milestone on the path to human PET imaging. The method, which transforms [18F]fluoride into an electrophilic fluorination reagent, provides access to aryl–18F bonds that would be challenging to synthesize via conventional radiochemistry methods.