Theoretical Study on Copper-Catalyzed S-Arylation of Thiophenols with Aryl Halides: Evidence Supporting the LCu(I)-SPh Active Catalyst and Halogen Atom Transfer Mechanism

Abstract

A systematic theoretical study on reaction mechanisms for copper-catalyzed Ullmann S-arylation reactions of thiophenols with aryl halides is reported herein. The equilibriums and consequent relative concentrations of possible copper species in the reaction solution were carefully evaluated to determine the most probable active catalytic forms. Subsequently, reactivity studies of these copper species with aryl halides were performed in the context of several commonly proposed mechanisms for copper(I)-catalyzed Ullmann reactions, such as oxidative addition/reductive elimination, σ-bond metathesis, single electron transfer (SET), and halogen atom transfer (HAT) mechanisms. On the basis of these intensive studies, we propose for the f irst time that the active copper catalyst should be neutral (L)Cu(I)-SAr species (L denotes a neutral ancillary ligand; SAr denotes a thiophenolato type ligand) in nonpolar or less polar solvent and anionic Cu(SAr) 2  species in highly polar solvent. These two kinds of species are in equilibrium with each other. For both copper species, the HAT mechanism is the most favored among all the possible mechanisms examined. Under the HAT mechanism, a critical halogen atom transfer from aryl halide to Cu(I) center occurs and accordingly involves the formation of intermediate Cu(II)(SAr)(X) (X denotes a halide ligand) species as well as an aryl radical. Subsequent direct and rapid attack of the aryl radical to the thiophenolato ligand in Cu(II)(SAr)(X) delivers the coupling product. Aryl halide substrate effect studies reveal that various kinds of aryl halides follow the reactivity trend of ArI > ArBr > ArCl under this HAT mechanism. This trend prediction is in good agreement with experimental observations that aryl iodides are generally more reactive than aryl bromides and chlorides for such Ullmann S-arylation reactions and thus lends further support for this HAT mechanism. Given the mechanistic proposals for Ullmann N-and O-arylation reactions, Ullmann S-arylation reactions should probably follow an analogous mechanism to that of O-arylation reactions, which is in distinct contrast with the oxidative addition mechanism proposed for N-arylation reactions. This highlights once again that the reaction mechanism of such copper(I)-catalyzed Ullmann reactions is dependent on the nature of the nucleophiles employed. Nucleophiles with reactive centers from different groups in the periodic table may possibly be involved in different mechanisms, and vice versa. These insights should therefore be valuable for the understanding of the mechanism of Ullmann S-arylation reactions and further development of orthogonal or selective Ullmann reactions involving multifunctional nucleophiles.

Understanding the Heteroatom Effect on the Ullmann Copper-Catalyzed Cross-Coupling of X-Arylation (X = NH, O, S) Mechanism

“…The Gibbs energies computed for the formation of the complexes [(phen)Cu I (XPh)] follow the trend according to the pK a of the nucleophiles, i.e., pK a (PhNH 2 ) = 27.0, pK a (PhOH) = 9.95, and pK a (PhSH) = 6.5. In concordance with the experiments outcomes [60,65] [66,67], Chen et al [42], and Zhang et al [59][60][61]. Our results show that this disproportionation is unfavorable in nonpolar solvents while it becomes favored when the dipolar constant of the solvent increases, in good agreement with previously reported results [59][60][61].…”

“…As it was reported elsewhere [57,60,64], there are many copper species that can be formed depending on the reaction conditions. The disproportionation process usually leads to inactive species.…”

“…Halogen Atom Transfer HAT has been suggested to govern the mechanism in the reaction of O-and S-arylations [59,60]. In this route, PhI transfers the iodine atom to the [(phen)Cu I model [78][79][80] for the SET coupled with the cleavage of the Ph-I bond (see the Supplementary Materials pages S2-S4 for details) [51].…”

“…A strong effect of the solvent is observed trigged by the stabilization of the iodine anion, as can be observed from entries 7 and 8 of Table 2. Halogen Atom Transfer HAT has been suggested to govern the mechanism in the reaction of Oand S-arylations [59,60]. In this route, PhI transfers the iodine atom to the [(phen)Cu I The two-electron reaction mechanisms MET and OA-RE pathway were considered.…”

“…Conversely, Buchwald and Houk by experimental and computational methods claimed that the SET and HAT mechanisms are energetically more favorable for Ullmann N-and O-arylation of alkyl amines and alcohols with aryl iodides [51]. Further support to these one-electron mechanisms was given by a number of detailed theoretical studies on the N-, O-, and S-arylation reported by Zhang and co-workers [57][58][59][60][61]. They confirmed that [(L)Cu I (Nu)] species is indeed the most reactive towards aryl halide among all the other possible copper species.…”