Fluorine is the most electronegative element in the periodic table. When bound to carbon it forms the strongest bonds in organic chemistry and this makes fluorine substitution attractive for the development of pharmaceuticals and a wide range of speciality materials. Although highly polarised, the C–F bond gains stability from the resultant electrostatic attraction between the polarised Cδ+ and Fδ– atoms. This polarity suppresses lone pair donation from fluorine and in general fluorine is a weak coordinator. However, the C–F bond has interesting properties which can be understood either in terms of electrostatic/dipole interactions or by considering stereoelectronic interactions with neighbouring bonds or lone pairs. In this tutorial review these fundamental aspects of the C–F bond are explored to rationalise the geometry, conformation and reactivity of individual organofluorine compounds.

Understanding organofluorine chemistry. An introduction to the C–F bond

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

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Introduction of Fluorine and Fluorine-Containing Functional Groups

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. But the formation of carbon-fluorine bonds in complex molecules is a significant challenge. Here we discuss reactions to make organofluorides that have emerged within the past few years and which exemplify how to overcome some of the intricate challenges associated with fluorination.

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Catalysis for fluorination and trifluoromethylation

“All new is well-forgotten old”, the proverb goes. The current “fluorine boom” is news only to a novice in the field: the exceptional importance of fluorinated organic compounds in numerous areas has been known for a long time. The sharpest increase in the number of fluorine-containing pharmaceuticals and agrochemicals is dated back to 30 years ago. Also around that time (1979), the first monograph devoted to industrial applications of organofluorine compounds was published, covering not only fluorine-containing biologically active materials but also refrigerants, propellants, surfactants, textile chemicals, polymers, and dyes. The increasingly broad realization of the key role of organofluorine compounds in numerous areas has recently attracted many new scientists to the field. The development of new methods for the selective introduction of fluorine and fluorinecontaining groups into organic molecules for biologically active and other useful materials has become a hot area. Over 100 reviews, book chapters, and highlights on this subject have appeared in the literature in the past few years. As citing all of these publications in this review article is impossible, we provide references to only the most recent, general, and comprehensive ones. Molecules bearing a trifluoromethyl group constitute one of the most important classes of selectively fluorinated compounds. As early as 1928, Lehmann reported his observations of biological activity of some trifluoromethylated organic derivatives and already in 1959 Yale published a detailed review article entitled “The Trifluoromethyl Group in Medicinal Chemistry”. Since then, numerous books and reviews have appeared in the literature covering various aspects of trifluoromethylated organic and organometallic compounds. Within this family, derivatives bearing the CF3 group on aromatic rings are particularly numerous and important. Some examples of such compounds used as active ingredients of pharmaceuticals and agrochemicals are shown in Scheme 1. Trifluoromethylated building blocks and intermediates are clearly needed to make such molecules. The simplest trifluoromethylated aromatic compound, benzotrifluoride, was originally prepared by Swarts at the end of the 19th century. In his work, Swarts treated benzotrichloride with “two thirds of its weight of antimony fluoride” to obtain a mixture of PhCF2Cl and PhCF3, from which the two were separated and isolated pure by distillation. In the early 1930s, two industrial groups, one from Kinetic Chemicals, Inc. and one from I. G. Farbenindustrie AG patented their discoveries on the successful use of HF instead of SbF3 for the Swarts reaction. These inventions were the starting point for the modern large-scale manufacturing of trifluoromethylated aromatics. Other methods have been developed for conversion of various C1 units on the ring to CF3 with a variety of fluorinating agents. While representing an outstanding discovery and a classic of organic and organofluorine chemistry, the Swarts reaction is nonetheless neither atom-economical nor environmentally benign, as it deals with stoichiometric quantities of hazardous chemicals and generates large amounts of chlorine waste. To convert a CH3 group on the ring to CF3, the methyl is first exhaustively chlorinated to produce 3 equiv of HCl as a

Aromatic Trifluoromethylation with Metal Complexes

Recent years have seen considerable progress in the development of microfabricated systems for use in the chemical and biological sciences. Much development has been driven by a need to perform rapid measurements on small sample volumes. However, at a more primary level, interest in miniaturized analytical systems has been stimulated by the fact that physical processes can be more easily controlled and harnessed when instrumental dimensions are reduced to the micrometre scale. Such systems define new operational paradigms and provide predictions about how molecular synthesis might be revolutionized in the fields of high-throughput synthesis and chemical production.

https://www.gene-quantification.de/nature-review-3-lab-on-chip-2006.pdf

Control and detection of chemical reactions in microfluidic systems

General discussion of organic fluorine chemistry Preparation of highly fluorinated compounds Partial or selective fluorination The influence of fluorine of fluorocarbon groups on some reaction centres Nucleophilic displacement of halogen from fluorocarbon systems Elimination reactions Polyfluoroalkanes, polyfluoroalkenes, and derivatives Functional compounds containing oxygen, sulphur, or nitrogen and their derivatives Polyfluoroaromatic compounds Organometallic reagents References Index

Fluorine in Organic Chemistry

Microreactors for elemental fluorine

Partial table of contents: Lewis Acid Properties of Fluorinated Noble Gas Cations (G. Schrobilgen). Controlled Replacement of Fluorine by Oxygen in Fluorides and Oxyfluorides (K. Christe, et al.). Transition Metal Derivatives of Strong Protonic Acids and Superacids (F. Aubke, et al.). Fluorine Stabilized Carbon--Sulfur Multiple Bonding (K. Seppelt). A New Synthetic Procedure for the Preparation and Manufacture of Perfluoropolyethers (R. Lagow, et al.). Universal Synthesis of Perfluorinated Organic Compounds (J. Adcock). Electrophilic Fluorination Reactions with F 2 and Some Reagents Directly Derived from It (S. Rozen). Fluorination with Onium Poly(Hydrogen Fluorides): The Taming of Anhydrous Hydrogen Fluoride for Synthesis (G. Olah & X. Li). Index.

Synthetic fluorine chemistry

Continuous flow gas-liquid thin film microreactors have been effectively used for the selective fluorination of a range of 1,3-dicarbonyl and aromatic substrates and, additionally, the conversion of aromatic disulfides to the corresponding sulfur pentafluorides. Scale-up was demonstrated by the application of a three channel microreactor device fabricated by replication of a single channel system.

Richard D. Chambers

Papers

Fluorine in Organic Chemistry

Microreactors for elemental fluorine

Synthetic fluorine chemistry

Elemental fluorine. Part 13. Gas-liquid thin film microreactors for selective direct fluorination.

Direct fluorination of 1,3-dicarbonyl compounds☆☆☆