Bis- and Oligo(trifluoromethyl)benzenes: Hydrogen/Metal Exchange Rates and Gas-Phase Acidities

Abstract

Abstract:The proton mobilities (kinetic acidities) of bis-and tris(trifluoromethyl)benzene are dictated to a large extent by steric factors; the trifluoromethyl group is a fairly bulky substituent that can seriously impede the approach of the metalating reagent. Most satisfactory results in terms of yields and selectivities have been achieved with lithium 2,2,6,6-tetramethylpiperidide or with methyllithium in the presence of potassium tert-butoxide, a slim version of the standard superbase. The rates of deprotonation under irreversible conditions do not parallel the thermodynamic (equilibrium) acidities. Substituent effects on the deprotonation energies in the gas phase appear to be additive: each trifluoromethyl group lowers it by 13 kcal mol À1 when located ortho with respect to the carbanion, and by 10 kcal mol À1 when located in a meta or para position.

The Organometallic Approach to Molecular Diversity − Halogens as Helpers

“…Optional site selectivity: steric congestion by trialkylsilyl groups to direct metalations from a position adjacent to nitrogen to one remote from nitrogen Trifluoromethyl-and chloro-substituted substrates often exhibit optional site selectivities. The O-methoxymethoxy-protected 3-(trifluoromethyl)phenol (17; OR ϭ OCH 2 OCH 3 ), [18] 1,3-bis(trifluoromethyl)benzene, [27,28] 3-fluorobenzotrifluoride, [27,29] 3-chlorobenzotrifluoride, [30] and 2,4-dichloro-1-fluorobenzene, [31] when treated with the superbase, invariably undergo deprotonation at the position flanked by the two acidifying electronegative groups (Scheme 6). On the other hand, sec-butyllithium or lithium 2,2,6,6-tetramethylpiperidide (''LITMP") preferentially, if not exclusively, attack the CF 3 -remote 4-position [18,27Ϫ30] (Scheme 6).…”

“…The LIC-KOR superbase deprotonates 3-fluorobenzotrifluoride (19) exclusively at the doubly activated 2-position, [27] whereas PMDTA complexed sec-butyllithium metalates the 2-and the 4-positions in a ratio of 1:4. [28,29] 3-Chlorobenzotrifluoride (20) reacts with butyllithium, either in the presence or in the absence of potassium tert-butoxide, at the 2-position and with sec-butyllithium at the 4-position. [30] A proton is abstracted from the 3-position of 2,4-dichloro-1-fluorobenzene (21) when the superbase is employed (at Ϫ75°C ), and from the 6-position when sec-butyllithium is used (at Ϫ100°C), the corresponding derivatives being isolated after carboxylation in 74 and 92% yields, respectively, and with regioselectivities exceeding 99% [31] (Scheme 6).…”

Substituent effects on the relative rates and free energies of ortho-lithiation reactions: families of fluorobenzenes as the substrates

“…44 In contrast, the heavy halogen atoms chlorine, bromine and iodine are far less effective when accommodated at para rather than at meta positions. As previously observed in the case of methoxy using LIS, 45 fluorine and methoxy may even retard metalation.…”

Fluoro- or Trifluoromethyl-Substituted Benzyl and Phenethyl Alcohols: Substrates for Metal-Mediated Site-Selective Functionalization

“…When moving the deprotonation site from the ortho through the meta to the para position, the activating effect of fluorine drops by roughly half with each step, [7] whereas the effect of a trifluoromethyl group is almost position-invariant. [8] This differ- [a] Section de Chimie et génie chimique, EPF BCh,…”

“…When moving the deprotonation site from the ortho through the meta to the para position, the activating effect of fluorine drops by roughly half with each step, [7] whereas the effect of a trifluoromethyl group is almost position-invariant. [8] This differ- [ and phenethyl alcohols remains nevertheless an attractive option because of its operational simplicity. All three (trifluoromethyl)benzyl alcohols and two of the three (trifluoromethyl)phenethyl alcohol isomers were successfully submitted to the metalation/functionalization sequence.…”