Synthetic Strategies of Organofluorine Compounds

Introduction

The incorporation of fluorine atoms or fluorinated moieties into an organic compound can often lead to profound changes of the latter's physical, chemical, and biological properties such as metabolic stability, lipophilicity, and permeability. These unique properties make organofluorine compounds have great application value in pharmaceuticals and agricultural chemicals. In addition, organofluorine compounds can also be used in a variety of fields such as smartphone liquid crystal displays, photovoltaic solar cells, Teflon tapes and the coatings of textiles and buildings ^[1]. Although organofluorine compounds have huge market demand, application value and research value, the naturally occurring organofluorine compounds are rare, and almost all organofluorine compounds are synthetic. It can be said that organofluorine chemistry is virtually a completely man-made branch of organic chemistry. Therefore, understanding and further developing efficient organofluorine compounds synthetic strategies is an essential skill for every researcher in the field of organofluorine chemistry. Here, Alfa Chemistry briefly introduces the synthetic strategies of oorganofluorine compounds.

Synthetic Strategies

Methods for the synthesis of organofluorine compounds are roughly classified into two basic strategies: the fluorination and fluoroalkylation method and the building-block method.

• Fluorination and fluoroalkylation method: The method involves the direct introduction of fluorine or fluorinated moieties on the non-fluorine substrate by fluorination reagents or fluoroalkylation reagents to produce the required organofluorine compounds. Common fluorination reagents include various inorganic fluorides such as anhydrous HF, SbF₃, KF, BF₃, tetrafluoroborates, F₂, and CoF₃ ^[1-2]. However, these are gradually not considered as the first choice because of their high corrosive or explosive. Nowadays, the more user-friendly fluorination reagents are also quickly developed and they include HF derivatives, N,N-diethylaminosulfur trifluoride (DAST), bis(2-methoxyethyl)-aminosulfur trifluoride (Deoxo-Fluor), PhenoFluor and PyFluor, hydrogen-bonded tetrabutylammonium fluoride (TBAF) complexes, Selectfluor and N-fluorobenzenesulfonimide (NFSI) ^[2]. The commonly used fluoroalkylation reagents include monofluoroalkylation reagents, difluoroalkylation reagents, trifluoromethylation reagents, trifluoromethylthiolation reagents, trifluoromethoxylation reagents, defluorofunctionalization reagents, and so on. And each class of fluoroalkylation reagents contains many products, which will not be detailed here. You can browse our product list of fluoroalkylation reagents to learn more.
• Building block method: The building block method involves the synthesis of fluorine-containing target molecules by appropriate chemical conversion of fluorine-containing intermediates or small molecules (building blocks). This method can also be regarded as the synthesis of organofluorine compounds by organofluorine compounds. The number and type of fluorinated building blocks used in the synthesis of organofluorine compounds are very large and constantly expanding. According to the different functional group, the type of fluorinated building blocks includes fluoroalkanes, fluoroalkenes, fluoroalkynes, fluorinated aliphatic cyclic hydrocarbons, aromatic fluorocarbons, fluorinated carbonyl compounds, fluorinated alcohols, fluorinated carboxilic acids and derivatives, fluorinated amines, fluorinated ethers, fluorinated cyclic ethers and fluorinated heterocycles and many others. You can check out our product list of fluorinated building blocks for details.

Depending on the target molecule, only one of these methods may be applicable; and sometimes both may be needed.

Advantages and Disadvantages of Two Strategies

• Fluorination and fluoroalkylation method is a straightforward method for the introduction of fluorine atoms into target molecules, especially when the fluorination can be carried out with high regio- and chemoselectivities ^[3]. However, the handling of such reagents, especially fluorination reagents, requires special apparatus and techniques, and needs care, as the reagents are usually extraordinarily reactive and toxic. Moreover, these reagents are expensive, and some reaction conditions are violent and difficult to control.
• Generally, the building block method does not involve the fracture and formation of the C-F bond, so the reaction conditions are mild, the operation is relatively simple and safe, and no special equipment and technology are required. Thus, this approach is more familiar to synthetic chemists. However, fluorine substitution very often causes abnormal behavior with regard to the reactivity and/or selectivity of these building blocks relative to that of their nonfluorinated counterparts, thus providing a challenge to synthetic chemists to overcome these fluorine effects ^[3].

As a leading global supplier of organofluorine compounds, a wide range of both fluorination and fluoroalkylation reagents and fluorinated building blocks are available commercially nowadays from Alfa Chemistry. If you cannot find the reagent you are looking for, Alfa Chemistry also offers you with custom synthesis service and fluorination and fluoroalkylation reagents development service.

References

1. Britton R., et al. Contemporary synthetic strategies in organofluorine chemistry[J]. Nature Reviews Methods Primers, 2021, 1(1): 47.
2. Ni C., et al. Good partnership between sulfur and fluorine: sulfur-based fluorination and fluoroalkylation reagents for organic synthesis[J]. Chemical Reviews, 2015, 115(2): 765-825.
3. Shimizu M. AND Hiyama T. Modern synthetic methods for fluorine‐substituted target molecules[J]. Angewandte Chemie International Edition, 2005, 44(2): 214-231.