Why •CF<sub>2</sub>H is nucleophilic but •CF<sub>3</sub> is electrophilic in reactions with heterocycles.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38821941.
- Also identified by DOI 10.1038/s41467-024-48949-z and PMC identifier 11143314.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Radical substitution is a useful method to functionalize heterocycles, as in the venerable Minisci reaction. Empirically observed regiochemistries indicate that the CF<sub>2</sub>H radical has a nucleophilic character similar to alkyl radicals, but the CF<sub>3</sub> radical is electrophilic. While the difference between •CH<sub>3</sub> and •CF<sub>3</sub> is well understood, the reason that one and two Fs make little difference but the third has a large effect is puzzling. DFT calculations with M06-2X both reproduce experimental selectivities and also lead to an explanation of this difference. Theoretical methods reveal how the F inductive withdrawal and conjugative donation alter radical properties, but only CF<sub>3</sub> becomes decidedly electrophilic toward heterocycles. Here, we show a simple model to explain the radical orbital energy trends and resulting nucleophilicity or electrophilicity of fluorinated radicals.