Opening a Pandora’s Flask on a Prototype Catalytic Direct Arylation Reaction of Pentafluorobenzene: The Ag₂CO₃/Pd(OAc)₂/PPh₃ System

Abstract

Direct C–H functionalization reactions have opened new avenues in catalysis, removing the need for prefunctionalization of at least one of the substrates. Although C–H functionalization catalyzed by palladium complexes in the presence of a base is generally considered to proceed by the CMD/AMLA-6 mechanism, recent research has shown that silver(I) salts, frequently used as bases, can function as C–H bond activators instead of (or in addition to) palladium(II). In this study, we examine the coupling of pentafluorobenzene 1 to 4-iodotoluene 2a (and its analogues) to form 4-(pentafluorophenyl)toluene 3a catalyzed by palladium(II) acetate with the commonplace PPh 3 ligand, silver carbonate as base, and DMF as solvent. By studying the reaction of 1 with Ag 2 CO 3 /PPh 3 and with isolated silver (triphenylphosphine) carbonate complexes, we show the formation of C–H activation products containing the Ag(C 6 F 5 )(PPh 3 ) n unit. However, analysis is complicated by the lability of the Ag–PPh 3 bond and the presence of multiple species in the solution. The speciation of palladium(II) is investigated by high-resolution-MAS NMR (chosen for its suitability for suspensions) with a substoichiometric catalyst, demonstrating the formation of an equilibrium mixture of Pd(Ar)(κ 1 -OAc)(PPh 3 ) 2 and [Pd(Ar)(μ-OAc)(PPh 3 )] 2 as resting states (Ar = Ph, 4-tolyl). These two complexes react stoichiometrically with 1 to form coupling products. The catalytic reaction kinetics is investigated by in situ IR spectroscopy revealing a two-term rate law and dependence on [Pd tot /nPPh 3 ] 0.5 consistent with the dissociation of an off-cycle palladium dimer. The first term is independent of [ 1 ], whereas the second term is first order in [ 1 ]. The observed rates are very similar with Pd(PPh 3 ) 4 , Pd(Ph)(κ 1 -OAc)(PPh 3 ) 2 , and [Pd(Ph)(μ-OAc)(PPh 3 )] 2 catalysts. The kinetic isotope effect varied significantly according to conditions. The multiple speciation of both Ag I and Pd II acts as a warning against specifying the catalytic cycles in detail. Moreover, the rapid dynamic interconversion of Ag I species creates a level of complexity that has not been appreciated previously.

Applications of Transition Metal-Catalyzed ortho-Fluorine-Directed C–H Functionalization of (Poly)fluoroarenes in Organic Synthesis

“…It was not until 2016 that it was discovered that this assumption did not apply to silver salts. In several cases, it has now been proven that silver salts catalyze H/D exchange in fluorobenzenes and that Ag­(I) can act as the C–H bond activator in C–H functionalization instead of, or in competition with, palladium. − Silver carbonate, often used as a base, is highly insoluble in all common solvents, but is solubilized by coordination to phosphines. Dinuclear silver carbonate complexes may be isolated with coordinated phosphine. , Moreover, Ag 2 CO 3 reacts with pentafluorobenzene in the presence of the bulky phosphine XPhos to form isolable mononuclear [Ag­(C 6 F 5 )­(Xphos)] which reacts with a palladium aryl to form a biaryl below room temperature.…”

“…For example, [Ag­(C 6 F 5 )­(Xphos)] and [{Ag­(XPhos)} 2 (CO 3 )] are moderately labile and undergo exchange with free phosphine on a time scale of seconds . On the other hand, the corresponding triphenylphosphine complexes [Ag­(C 6 F 5 )­(PPh 3 ) n ] and [{Ag­(PPh 3 ) 2 } 2 (CO 3 )] are so labile that they defy characterization in solution . At present, little is known about the regioselectivity of silver-catalyzed reactions or their mechanisms.…”