“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 advances (1995–2005) in fluorinated pharmaceuticals based on natural products ☆

Fluorinated analogues of the canonical α-L-amino acids have gained widespread attention as building blocks that may endow peptides and proteins with advantageous biophysical, chemical and biological properties. This critical review covers the literature dealing with investigations of peptides and proteins containing fluorinated analogues of the canonical amino acids published over the course of the past decade including the late nineties. It focuses on side-chain fluorinated amino acids, the carbon backbone of which is identical to their natural analogues. Each class of amino acids—aliphatic, aromatic, charged and polar as well as proline—is presented in a separate section. General effects of fluorine on essential properties such as hydrophobicity, acidity/basicity and conformation of the specific side chains and the impact of these altered properties on stability, folding kinetics and activity of peptides and proteins are discussed (245 references).

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Fluorinated amino acids: compatibility with native protein structures and effects on protein–protein interactions

Trifluoromethylation of aryl and heteroaryl halides

This review analyzes the inherent scientific challenges of realizing the potential of storing solar energy by photochemical generation of high-energy metastable compounds whose subsequent thermal isomerization releases large amounts of low-temperature (<500 K) heat. Such compounds may be stored at room temperature for days or months, regenerated using sunlight, and may be cycled many times without significant degradation. After highlighting some of the general challenges of solar energy conversion and storage, we discuss how recent advances in understanding the effect of molecular strain on the thermal and photochemical reactivity of small molecules offers new opportunities for a systematic approach to the molecular design of solar thermal fuels, defining the molecular properties which determine the fundamental limits of such a material's performance characteristics.

Chemical solutions for the closed-cycle storage of solar energy

Reactions of trifluoromethyl ketones. IX. Investigation of the steric effect of a trifluoromethyl group based on the stereochemistry on the dehydration of trifluoromethyl homoallyl alcohols

Trifluoromethyl (CF3)-substituted donor–acceptor norbornadiene (NBD) derivatives were synthesized. The photoisomerization of CF3-NBD derivatives proceeded smoothly. The thermal stability of quadricyclane (QC) derivatives obtained from CF3-NBD derivatives was examined, and it was found that the CF3 group increased the thermal stability of the QC derivatives. Furthermore, CF3-NBD derivatives exhibited efficient fatigue resistance.

Trifluoromethyl-Substituted Donor–Acceptor Norbornadiene, Useful Solar Energy Material

In the study of ene reaction of trifluoromethyl ketones, a trifluoromethyl group was found to behave as a much larger substituent than commonly believed. Similar results were obtained in the dehydration of trifluoromethyl homoallyl alcohols.

The steric effect of a trifluoromethyl group.

Reaction of trifluoromethyl ketones. V. Dehydration of trifluoromethylated homoallyl alcohols. Synthesis of trifluoromethylated dienes.

Polymers containing trifluoromethyl (CF3)-substituted donor−acceptor NBD moieties in the side chain or in the main chain were synthesized by substitution or addition of a CF3−NBD−carboxylic acid derivative or by polycondensation of a CF3−NBD−dicarboxylic acid derivative. The photoisomerization of the NBD moieties in these polymers proceeded very smoothly to give the corresponding QC moieties. Furthermore, the NBD moieties exhibited efficient fatigue resistance.

Takabumi Nagai

Papers

Reactions of trifluoromethyl ketones. IX. Investigation of the steric effect of a trifluoromethyl group based on the stereochemistry on the dehydration of trifluoromethyl homoallyl alcohols

Trifluoromethyl-Substituted Donor–Acceptor Norbornadiene, Useful Solar Energy Material

The steric effect of a trifluoromethyl group.

Reaction of trifluoromethyl ketones. V. Dehydration of trifluoromethylated homoallyl alcohols. Synthesis of trifluoromethylated dienes.

Synthesis of New Photoresponsive Polymers Containing Trifluoromethyl-Substituted Norbornadiene Moieties