Electrophilic Trifluoromethylation

Electrophilic Trifluoromethylation

Overall Score4
  • Generality
  • Reagent Availability
  • Experimental User Friendliness
  • General Characteristics

Fluorine and hydrogen are about the same size, but are electronically very different. The substitution of hydrogen atoms with fluorine atoms is a common way of tuning the electronic property of molecules without substantially affecting their size. In particular, trifluoromethyl (CF3) group is an important functional group in drug development.

The introduction of CF3 group is roughly divided into two approaches: nucleophilic conditions (the Ruppert-Prakash method) and electrophilic/free radical conditions.

For the latter, many new useful reagents have been developed in the past few years. Representative examples are shown below.


  • General References

<General Reviews>

<Umemoto’s reagent>

<Togni’s reagent>

  • Eisenberger, P.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, 2579. DOI: 10.1002/chem.200501052
  • Kieltsch, I,; Eisenberger, P.; Togni, A. Angew. Chem. Int. Ed. 2007, 46, 754. DOI: 10.1002/anie.200603497
  • Eisenberger, P.; Kieltsch, I.; Armanino, N.; Togni, A. Chem. Commun. 2008, 1575. DOI: 10.1039/B801424H
  • Stanek, K.; Koller, R.; Togni, A. J. Org. Chem. 2008, 73, 7678. DOI: 10.1021/jo8014825
  • Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Angew. Chem. Int. Ed. 2009, 48, 4332. DOI: 10.1002/anie.200900974
  • Eisenberger, P.; Kiltsch, I.; Koller, R.; Stanek, K.; Togni, A. Org. Synth. 2011, 88, 168. [PDF]

<Shibata-Johnson reagent>

  • Noritake, S.; Shibata, N.; Nakamura, S.; Toru, T.; Shiro, M. Eur. J. Org. Chem. 2008, 3465. DOI: 10.1002/ejoc.200800419

<Langlois/Baran’s reagent>

  • Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991, 32, 7525. doi:10.1016/0040-4039(91)80524-A
  • Ji, Y.; Bruecki, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. USA 2011, 108, 14411. doi: 10.1073/pnas.1109059108
  • Fujiwara, Y.; Dixon, J.A.; Rodriguez, R.A.; Baxter, R.D.; Dixon, D.D.; Collins, M.R.; Blackmond, D.G.; Baran, P.S. J. Am. Chem. Soc. 2012, 134, 1494. DOI: 10.1021/ja211422g
  • Fujiwara, Y.; Dixon, J.A.; O’Hara, F.; Daa Funder, E.; Dixon, D.D.; Rodriguez, R.A.; Baxter, R.D.; Herle, B.; Sach, N.; Collins, M.R.; Ishihara, Y.; Baran, P.S. Nature 2012, 492, 95. doi:10.1038/nature11680
  • Ye, Y.; Kunzi, S. A.; Sanford, M. S. Org. Lett. 2012, 14, 4979. DOI: 10.1021/ol3022726
  • Reaction Mechanism

Since the carbon atom of CF3 group is surrounded by electronegative fluorine atoms, it is not particularly reactive towards substitution via backside attack (SN2 reaction).

  • Examples

  • Experimental Procedure

  • Experimental Tips

  • References

  • Related Reactions

Amii Trifluoromethylation 

Nucleophilic Fluoroalkylation

Burton Trifluoromethylation

Electrophilic Fluorination Reagent

Balz-Schiemann Reaction


  • Related Books

  • External Links

Nucleophilic and Electrophilic Trifluoromethylation (PDF)

フッ素化反応(Sigma-Aldrich, PDF)


Trifluoromethylation – Wikipedia

Sodium trifluoromethanesulfinate – Wikipedia

Fluorination Strategies and Methodologies (PDF)