Mechanism of Trifluoromethylation of Aryl Halides with CuCF₃ and the Ortho Effect

Abstract

A combined experimental (radical clock, kinetic, Hammett) and computational (DFT, MM) study of the trifluoromethylation reaction of aryl halides with CuCF3 reveals a nonradical mechanism involving Ar-X oxidative addition to the Cu(I) center as the rate determining step. The reaction is second order, first order in each reactant with ΔG(⧧) ≈ 24 kcal/mol for PhI (computed ΔG(⧧) = 21.9 kcal/mol). An abrupt change in the gradient on the Hammett plot of log(kR/kH) versus σp for 11 p-RC6H4I substrates produces two correlations (ρ = +0.69 and +1.83), which is temptingly suggestive of two different reaction pathways. Only one mechanism is operational, however, as advocated by a single linear correlation with σp(-) (ρ = +0.91), analysis of the experimental ρ values, close similarity of the transition states varying in R and displaying clear signs of -M interactions, and excellent reproduction of the plot by DFT. The long-known yet previously uncomprehended ortho effect has been quantified, for the first time, using the reaction of CuCF3 with a series of o-RC6H4Br: R(kR/kH) = H (1) < Me (3.5) < MeO (4) < CN (20) < CHO (250) < CO2Me (850) < NO2 (4300) < Ac (7300) < CO2H (150 000). With minor contributions from electronic factors, the ortho effect is largely determined by (i) the stabilizing coordination of the o-substituent to Cu in the transition state with the Cu···O distance varying directly with the barrier and (ii) the steric bulk of the o-substituent that raises the ground state free energy of the haloarene (G(o)ortho - G(o)H or G(o)ortho - G(o)para) by inflicting molecular strain and consequently weakening the Ar-X bond.

A catalytic fluoride-rebound mechanism for C(sp 3 )-CF 3 bond formation

“…The broader mechanistic framework consisting of fluoride-rebound reductive elimination upon which this radiochemical reaction is built also has implications for the understanding of transition metal catalysis, as it seems possible that such a mechanism is in fact operative in the related copper-mediated protocols currently in use (in both radiochemical and nonradiochemical contexts) (46–48). Furthermore, this work suggests a promising direction for the development of organometallic reagents via catalytically…”

Access to trifluoromethylated 4-alkoxy-2-pyrones, pyridones and quinolones

“…A radical mechanism has been ruled out on the basis of experimental and computation data. 35 Thus iodinated methoxypyrone 6 was treated with MFSDA in the presence of copper (I) iodide in a number of anhydrous solvents (Table 1). When the reaction was carried out in THF and DMSO (Table 1, entries 1 & 2), no product was observed.…”

Well‐Defined CuC2F5 Complexes and Pentafluoroethylation of Acid Chlorides

“…This complex was expected to be tetrahedral [(Ph 3 P) 3 CuC 2 F 5 ], akin to the previously characterized CF 3 analogue [(Ph 3 P) 3 CuCF 3 ]. [4d] Unexpectedly, however, X-ray diffraction showed that the Cu atom in the isolated product Scheme 1.…”

“…However, CuCF 3 is not a welldefined compound but rather a variety of species of the general formula [L n CuCF 3 ], where L is a weakly bound ligand or a solvent molecule. [3] Fully characterized CF 3 Cu I complexes are very rare and only a handful of such compounds have been reported. [4] Synthetic methodologies for the introduction of the C 2 F 5 group into organic molecules are not nearly as developed as trifluoromethylation methods.…”

“…This reaction produces so-called "ligandless" CuC 2 F 5 , in which the Cu I center is stabilized by coordination with weakly bound DMF solvent molecules, Et 3 N released from the TREAT HF, and tBuOH coproduced in the cupration step (Scheme 1). [3,9,10] We reasoned that replacing these weakly coordinated molecules with stronger binding ligands might produce new isolable complexes of the type L n CuC 2 F 5 for full characterization and use in pentafluoroethylation reactions.…”