Donor-activated lithiation and sodiation of trifluoromethylbenzene: structural, spectroscopic and theoretical insights

Jennifer Garden, David Armstrong, William Clegg, Joaquin Garcia Alvarez, Eva Hevia, Alan Kennedy, Robert Mulvey, Stuart Robertson, Luca Russo

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Aiming to shed new light on the stability and constitution of the organometallic intermediates involved in direct ortho-metalation processes, using trifluoromethylbenzene (1) as a case study, this paper investigates the deprotonation of 1 using group 1 alkyl bases tBuLi and nBuNa in the presence of the Lewis donors TMEDA (N,N,N′,N′-tetramethylethylenediamine), THF, and PMDETA (N,N,N′,N″,N″-pentamethyldiethylenetriamine). A systematic and comprehensive study combining structural, spectroscopic, and theoretical studies reveals that these donors strongly influence the final outcome of the reactions, not only by activating the alkali-metal bases and facilitating deprotonation of 1 but also by tuning the regioselectivity of the reaction. Thus, while using tBuLi/TMEDA, ortho-metalation of 1 is preferred, switching to THF gives a complex mixture of products with the meta-regioisomer being the major species crystallizing from hexane solution. This donor effect is significantly reduced when nBuNa is employed, as ortho-regioselectivity is observed almost exclusively using THF, TMEDA, or PMDETA. DFT calculations computing the relative energies of the ortho-, meta-, and para-regioisomers obtained from these metalating systems have also been carried out. Reinforcing the experimental findings, these theoretical studies show that although in all cases the product of ortho-metalation is the most thermodynamically preferred, the energy difference between the three possible modeled regioisomers is much larger for the Na systems than for the Li ones. The structures of key reaction intermediates [(TMEDA)·Li(C6H4-CF3)]2 (2), [(TMEDA)·Na(C6H4-CF3)]2 (3), and [(PMDETA)·Na(C6H4-CF3)]2 (4) have been elucidated by X-ray crystallographic studies. All compounds exhibit a similar dimeric arrangement with a four-atom core constituting a {MCMC} ring. Interestingly for Na derivatives 3 and 4 unusual Na···F dative interactions are found, which appear to contribute to the overall stability of these compounds, therefore favoring ortho-metalation of 1, as the meta or para structures do not contain these additional interactions.
Original languageEnglish
Pages (from-to)5481-5490
Number of pages10
Issue number19
Early online date16 Sep 2013
Publication statusPublished - 2013


  • donor-activated lithiation
  • sodiation
  • trifluoromethylbenzene
  • spectroscopic
  • theoretical insights
  • structural


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