Aryl fluorinated building blocks refer to a series of aromatic compounds possessing one or several fluorine atoms directly attached to the aromatic ring skeleton. Fluorine can provide many beneficial properties when incorporated into an Aryl. Firstly, fluorinated arenes are more lipophilic than their non-fluorinated counterparts, which can be used to advantage in drug development. Furthermore, fluorine is sometimes used as an isostere for hydrogen in medicinal chemistry. In addition, fluorinated compounds can be strategically used as transition state inhibitors.
Fig.1. Aryl fluorinated building blocks
A fundamental challenge of any C−F bond forming reaction, regardless of the approach, is the nature of fluorine itself. The fluoride anion, due to its electronegativity and small ionic radius (1.33 Å), can form strong hydrogen bonds with a variety of hydrogen bond donors such as water, alcohols, amines, and amides. The high solvation energy of the fluoride ion in aqueous media results in a tightly bound hydration shell of water molecules around the ion. Therefore, fluoride is typically only weakly nucleophilic in the presence of hydrogen bond donors, and this attenuated nucleophilicity of fluoride limits access to C−F bonds via nucleophilic substitution reactions.
Approaches to Arene Fluorination
Traditional Nucleophilic Arene Fluorination Reactions: A primary challenge associated with traditional nucleophilic arene fluorination reactions is the limitation to relatively simple substrates, resulting from harsh reaction conditions and the strong bacisity of nucleophilic fluoride. In 1927, Balz and Schiemann developed a nucleophilic fluorination of arenes via thermal decomposition of aryl diazonium tetrafluoroborate salts (Fig 2).
Fig.2. Nucleophilic fluorination of aryl diazonium salts
Nucleophilic fluorination reactions: Nucleophilic fluorination is a simple but effective approach to improving nucleophilic arene fluorination that exclude water and other hydrogen bond donors that would attenuate fluoride’s nucleophilicity. Tetrabutylammonium fluoride (TBAF) is a common soluble fluoride source that is available as a trihydrate (Fig 3).
Fig.3. nucleophilic arene fluorination using TBAF
Nucleophilic deoxyfluorination of phenols: Along with aryl halides, phenols are attractive, readily available substrates for aryl fluoride synthesis. For example, catechols can be deoxyfluorinated with deoxo-fluor and then reduction with sodium borohydride (Fig 4).
Fig.4. Deoxyfluorination of catechols via a one-pot reaction
Electrophilic fluorination reactions: A complementary approach toward arene fluorination is to use aryl nucleophiles and an electrophilic fluorinating reagent. Even though N-fluoro reagents can formally behave as a source of fluoronium cations (F+), the commonly used electrophilic fluorinating reagents are shown in Fig 5.
Fig.5. Commonly used electrophilic fluorinating reagents
Aryl fluorinated building blocks are widely used as intermediates or end-product in the synthesis of pharmaceuticals, in which fluorine substitution can enhance potency and impact target selectivity by affecting pKa, modulating conformation, hydrophobic interactions and lipophilicity, or a combination of these properties. In addition to this, fluorinated aromatic compounds can be applied in insecticides, plastics and molecules related to liquid crystal technology.