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3.20 Asymmetric Fluorination, Monofluoromethylation, Difluoromethylation, and Trifluoromethylation Reactions

DOI: 10.1055/sos-SD-203-00543

Gouverneur, V.; Lozano, O.Science of Synthesis: Stereoselective Synthesis, (20113851.

General Introduction

In recent years, fluorine chemistry has established itself as an important area of research, which benefits agrochemical, medicinal, and material science.[‌1‌‌3‌] The properties of the CF bond assist in interpreting the behavior of organofluorine compounds.[‌4‌,‌5‌] For instance, fluorine is the most electronegative element (χ=4) and has the smallest atomic radius of the second row of the periodic table. Its ionization energy (I) is highly endothermic (401.2 kcal·mol1) but its electron affinity (Eea) is a very favorable exothermic process (+78.3 kcal·mol1). The fluorine atom is intermediate in size between hydrogen and oxygen but closer to oxygen [van der Waals radii (Å): H (1.20); O (1.52); F (1.47)]. Fluorine forms the strongest bond to carbon in organic chemistry (109.9 kcal·mol1 for CH3F) and is highly polarized with the electron density located mainly on fluorine. The substantial ionic nature of the CF bond is reflected in its large dipole moment, which, combined with other effects (hyperconjugation, weak hydrogen-bond acceptor, charge dipole interactions CFX+), accounts for the conformational behavior of many fluorinated compounds. These unique characteristics have encouraged direct fluorination, in the context of mono-, di-, and trifluoromethylation, as a means of tailoring the physical properties of organic compounds to demand. Selected characteristics of fluoromethanes are given in Table 1.

Table 1 Properties of Fluoromethanes[‌4‌]

CF Bond Length (Å) CF Bond Energy (kcal·mol1) bp (°C) Dipole Moment (D) Ref
CH4 161 0.0 [‌4‌]
CH3F 1.385 109.9 78 1.85 [‌4‌]
CH2F2 1.357 119.5 52 1.97 [‌4‌]
CF3H 1.332 127.5 83 1.65 [‌4‌]
CF4 1.319 130.5 128 0.0 [‌4‌]

More recent progress in organofluorine chemistry has led to the development of numerous novel catalytic methods for the fluorination of organic molecules, such as aromatics and alkenes.[‌6‌] Various transition-metal-catalyzed and organocatalytic strategies for the stereoselective introduction of a fluorine atom or fluorine-containing substituent into activated substrates have also been disclosed.[‌7‌,‌8‌] This chapter covers the stereoselective synthesis of compounds containing a fluorine bonded to an sp3-carbon atom (i.e. monofluoromethyl, difluoromethyl, or trifluoromethyl substituents). The emphasis is on highlighting previously discussed asymmetric routes inclusive of catalytic strategies of broad synthetic scope, and on disclosing key new developments that have not been presented in previous volumes of Science of Synthesis for the fluorination of aldehydes {see Science of Synthesis, Vol.25 [Aldehydes (Section 25.4.1.1.1.1)]}, ketones {see Science of Synthesis, Vol.26 [Ketones (Section 26.6.1)]}, acids and esters {see Science of Synthesis, Vol.20 [Three CarbonHeteroatom Bonds: Acid Halides; Carboxylic Acids and Acid Salts; Esters, and Lactones; Peroxy Acids and R(CO)OX Compounds; R(CO)X, X=S, Se, Te (Sections 20.2.8.1.1.1 and 20.5.11.1.1.1)]}, and substrates other than carbonyl derivatives [see Science of Synthesis, Vol.34 (Fluorine)]. For each subcategory of fluorinated compounds, the material is organized around the reactivity profile of the fluorinating reagent and the generic mode of activation and induction used to facilitate stereoselective fluorination.

References