Fluorinating agents

Reproduced Content

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 Agent	What 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 (S_N2)	Excellent atom economy	Extremely corrosive and hazardous
Fluoride Salts (e.g. KF, CsF)	Halide Displacements (S_N2)	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.

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.