Synthetic toolbox: C-F bond formation

Fluorinating agents

This page reproduces content from G. Pattison, 'Green' and Sustainable Halogenation Processes, in Green and Sustainable Medicinal Chemistry: Methods, Tools and Strategies for the 21st Century Pharmaceutical Industry, The Royal Society of Chemistry, 2016, ch. 17, pp. 203-217.. It is copyright to the Royal Society of Chemistry (RSC) and is reproduced here with their express permission. If you wish to reproduce it elsewhere you must obtain similar permission from the RSC.

Fluorinating agents are, by their inherent highly reactive nature, not generally regarded as green or sustainable due to associated hazards and toxicity issues.  However modern alternatives are being developed alongside safer handling techniques that facilitate safer halogenation reactions, with minimal impact on the environment.[1] Table 1 provides a summary of the main advantages and disadvantages of various fluorinating agents.[1] 

 

Fluorinating AgentWhat is it used to fluorinate?Why is it green?
Advantages
Why is it not green?
Disadvantages

Elemental Fluorine

Carbonyl compounds

Aromatics

C-H bonds

 

Excellent atom economy

Highly reactive, toxic

Specialist handling needed

Often generate HF byproducts

HF

Halide Displacements (SN2)

Excellent atom economy

Extremely corrosive and hazardous

Fluoride Salts (e.g. KF, CsF)

Halide Displacements (SN2)

Safe and easy to handle

Excellent atom economy

Few by-products produced

Very hygroscopic but often needs to be dry for good reactivity

N-F Reagents (e.g. Selectfluor, NFSI)

Carbonyl Compounds

Aromatics

Alkenes

Thioethers

Organometallic reagents (e.g. organotin)

Safe and easy to handle

Low toxicity

Derived from elemental fluorine

Expensive

Amine waste generated

Ruppert Reagent (CF3SiMe3)

Carbonyl compounds (nucleophilic)

Aromatics

Safe and easy to handle

Silicon-containing waste generated

Expensive

Electrophilic trifluoromethylation reagents (e.g. Togni)

Carbonyl compounds (electrophilic)

Aromatics

Alkenes

Alcohols/sulfides

Few other ways of doing many of these transformations

Iodoarene waste generated

Expensive

Reports of explosions

DAST / SF4

Alcohol → CF

Carbonyl → CF2

Few other ways of doing many of these transformations

Corrosive

Explosive byproducts at high temperatures

Fluoroform (CHF3)

Carbonyl compounds

Using byproduct of Teflon production which otherwise needs to be disposed of

Very potent greenhouse gas

Normally incinerated producing H2O, CO2, HF

Trifluoroacetate Salts

Aromatics

Carbonyl compounds

CO2 is only byproduct produced on decarboxylation

CO2 is greenhouse gas

Produced using corrosive HF

Table 1: Advantages and disadvantages of range of fluorinating agents.  Reproduced from [1] with permission from The Royal Society of Chemistry.

  1. G. Pattison, 'Green' and Sustainable Halogenation Processes, in Green and Sustainable Medicinal Chemistry: Methods, Tools and Strategies for the 21st Century Pharmaceutical Industry, The Royal Society of Chemistry, 2016, ch. 17, pp. 203-217.