and coworkers, DFT modeling studies on the special mechanistic features for the introduction of fluorine and fluoroalkyl groups are summarized with a particular focus on the catalytic reactions and application of the new fluorinating reagents. As mentioned above, application of organofluorines is particularly important in chemical industry. A large part of the commercially applied agrochemicals introduced in the last decade are fluorinated compounds. In Chapter 11 by Jeschke, the modern trends in design of fluorine‐containing compounds are described analyzing the most important classes of herbicides, fungicides, and insecticides. Fluorine‐18 labeling of positron emission tomography (PET) tracers is one of the most challenging areas in organofluorine chemistry. Application of new methodology and reagents is reviewed in Chapter 12 by Liang and coworkers.
This book is a result of a global collaboration by excellent research groups from Asia, Europe, and North America indicating worldwide efforts of the organofluorine community to forward this field, which is very important in synthetic and mechanistic research as well as in industrial applications. We would like to appreciate all authors of this book for their enthusiasm and for sharing their knowledge in organofluorine chemistry with the readers and their help in the realization of this book. In addition, the editors are indebted to the Knut och Alice Wallenbergs Foundation for granting the project “Organofluorines: anthropogenic small‐molecules for life sciences” (Dnr: 2018.0066).
Stockholm, April 2020
Kálmán J. Szabó
Stockholm University, Arrhenius Laboratory
Department of Organic Chemistry
Stockholm, Sweden
1 The Development of New Reagents and Reactions for Synthetic Organofluorine Chemistry by Understanding the Unique Fluorine Effects
Qiqiang Xieand Jinbo Hu
CAS Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling‐Ling Road, Shanghai, 200032, China
1.1 Introduction
For a long period of time, fluorine chemistry research was deemed to be very dangerous, in part owing to the notorious fluorination reagents such as F2 and HF, which are highly corrosive and reactive. In this context, synthetic organofluorine chemistry was only pursued by a handful of researchers for several decades after the first synthesis of F2 by Moissan in 1886. However, great changes had taken place over the past decades. With the successful application of chlorofluorocarbons (although banned later owing to their ozone‐depleting character by Montreal Protocol in 1987) as refrigerants, the development of high‐performance fluorinated materials such as Teflon and the development of fluorinated pharmaceuticals and agrochemicals, organofluorine chemistry has become increasingly important in satisfying the huge demand for fluorinated molecules with diverse functions [1]. To date, organofluorine chemistry has become an indispensable branch of organic chemistry and enriched many aspects of related areas such as medicinal chemistry and materials science, among others. Perhaps the most prominent application of organofluorine compounds that has close relation with our everyday life is fluorinated drugs. For example, among the 59 drugs (39 of them are small molecule drugs) approved by FDA in 2018, 18 contain at least one fluorine atom; among the 48 drugs approved by FDA in 2019, 13 contain at least one fluorine atom [2]. Some representative fluorinated drugs approved in 2018 and 2019 are shown in Figure 1.1.
In spite of the importance of fluorinated molecules in modern society, naturally occurring organofluorine compounds are rare [3]. Basically, all the commercially supplied organofluorine compounds are manmade. Thus, the development of new reagents and reactions to introduce fluorine atoms or fluorine‐containing moieties into organic molecules is one of the central goals in modern synthetic organofluorine chemistry.
Figure 1.1 Fluorinated drugs newly approved by FDA in 2018 and 2019.
Figure 1.2 Organofluorine reagents developed or co‐developed by us.
Over the past 15 years, our group has been interested in reaction mechanism‐inspired synthetic organofluorine chemistry [4]. We have developed or co‐developed a variety of reagents, including fluoroalkyl aryl sulfones [5], fluoroalkyl sulfoximines [6], fluoroalkyl heteroaryl sulfones [7], difluorocarbene reagents [8], fluorinated sulfinate salts [9], fluorinated esters [10], CpFluors [11], and SulfoxFluor [12], among others (for a review, see Ref. [4d]), for fluoroalkylation, fluoroolefination, and fluorination reactions (Figure 1.2). Our research program was triggered by two questions: (i) What are the unique features of organofluorine reactions (compared with regular organic reactions)? (ii) Is there any relationship among fluoroalkylation, fluoroolefination, and fluorination? In this review, we intend to answer these two questions by illustrating representative reagents and reactions developed (or co‐developed) by us. In particular, understanding of the unique fluorine effects in organic reactions is helpful in addressing these two questions [4g].
1.2 The Unique Fluorine Effects in Organic Reactions
It is now gradually accepted that organofluorine reactions are usually distinct from regular organic reactions, and in many cases, fluorine substitution in an organic molecule imparts unique reactivity to the latter. As a result, direct application of the knowledge and experience acquired from regular organic reactions to organofluorine reactions often leads to failure or unexpected results. In this section, we provide some selected examples to highlight the unique features of organofluorine reactions. For more examples and discussions, one may refer to our recent tutorial review [4e].
1.2.1 Fluorine‐Enabled Stability of “CuCF3” in Water, and the Unusual Water‐Promoted Trifluoromethylation
Organocopper reagents are widely used in organic synthesis [13]; however, these reagents are typically water sensitive. In 2012, we disclosed a water‐promoted trifluoromethylation of α‐diazo esters to access α‐trifluoromethyl esters, representing the first example of fluoroalkylation of a non‐fluorinated carbene precursor (Scheme 1.1) [14]. We found that “CuCF3” (prepared from CuI/CsF/TMSCF3) in n‐methyl‐2‐pyrrolidone (NMP) is stable even in the presence of 66 equiv of water at room temperature within five hours and only about 5% of “CuCF3” decomposed. Taking advantage of the unusual stability of “CuCF3” in water (fluorine effect), we could therefore use water (CuI is also applicable) as the iodide scavenger to enhance the activity of “CuCF3” prepared from CuI/CsF/TMSCF3 significantly by changing “CuCF3” in the form of [Cu(CF3)I]− to “ligandless” [Cu(CF3)], which is more reactive toward α‐diazo esters. From an organometallic chemistry point of view, water promotes the ligand exchange in “CuCF3” by eliminating iodide, making the ligation of α‐diazo esters to “CuCF3”
