Alkyl Fluorinated Building Blocks

Introduction

Alkyl fluorinated building blocks are a series of alkyl compounds substituted by fluorine atoms, which occur in a wide range of products. According to the number of fluorine substituents, they can be divided into monofluoro, polyfluoro and perfluorinated alkyl compounds. Current interest in fluorination chemistry is largely a consequence of the properties that fluorine substitution can impart on molecules, such as pharmaceuticals, agrochemicals, materials, and radiotracers for positron emission tomography. As many as 30-40% of agrochemicals and 20-25% of pharmaceuticals on the market are estimated to contain fluorine.

Fluorine is the most electronegative element and its properties can be distinctive in comparison to other organohalogens. The presence of a fluorine atom or a fluorinated group strongly affects the physical and chemical properties of a molecule such as chemical stability, biological activity and temperature resistance. The carbon-fluorine bond is one of the strongest in organic chemistry (an average bond energy around 480 kJ/mol), significantly stronger than the bonds of carbon with other halogens. Carbon-fluorine bond formation is a challenging chemical transformation largely due to fluorine’s high electronegativity and the high hydration energy of fluoride anion.

Synthesis methods

• Nucleophilic fluorination: The major alternative to electrophilic fluorination is using reagents that are sources of "F^-", for nucleophilic displacement typically of chloride and bromide. Metathesis reactions employing alkali metalfluorides are the simplest.

  R₃CCl + MF → R₃CF + MCl (M = Na, K, Cs)

• Electrophilic fluorination: Electrophilic fluorination needs a sources of "F⁺". The electrophilic fluorination agents often possessing feature N-F bonds, such as F-TEDA-BF₄. Asymmetric fluorination, whereby only one of two possible enantiomeric products are generated from a prochiral substrate, rely on electrophilic fluorination reagents (Scheme 1).

Scheme 1
(Chemical Reviews. 2006, 106 (7), 2943–2989)

• Deoxofluorination: Deoxofluorination agents achieve the replacement of hydroxyl and carbonyl groups with one and two fluoridations, respectively. For instance, sulfur tetrafluoride is a useful reagent for fluoride in carbonyl compounds.

  RCO₂H + SF₄ → RCF₃ + SO₂ + HF

Alternates to SF₄ include the diethylaminosulfur trifluoride (DAST, NEt₂SF₃) and bis(2-methoxyethyl) aminosulfur trifluoride (deoxo-fluor).

• From fluorinated building blocks: Many organofluorine compounds are generated from reagents that deliver perfluoroalkyl and perfluoroaryl groups. CF₃X (X = Br, I), C₆F₅Br and C₃F₇I are the representative among the available fluorinated building blocks which form Grignard reagents that then can be treated with a variety of electrophiles.

Applications

The alkyl fluorinated compounds are commonly applied in pharmaceuticals and agrochemicals because they are generally metabolically stable and fluorine acts as a bioisostere of the hydrogen atom. In addition, they can be utilized as fluoropolymers, refrigerants, surfactants, anesthetics, oil-repellents, catalysis, and water-repellents, among others.