Donor-Activated Lithiation and Sodiation of Trifluoromethylbenzene: Structural, Spectroscopic, and Theoretical Insights

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.