Transition-State Stabilization by Secondary Orbital Interactions between Fluoroalkyl Ligands and Palladium During Reductive Elimination from Palladium(aryl)(fluoroalkyl) Complexes

Abstract

Palladium-catalyzed fluoroalkylations of aryl halides are valuable reactions for the synthesis of fluorinated, biologically active molecules. Reductive elimination from an intermediate Pd(aryl)(fluoroalkyl) complex is the step that forms the C(aryl)− C(fluoroalkyl) bond, and this step typically requires higher temperatures and proceeds with slower rates than the reductive elimination of nonfluorinated alkylarenes from the analogous Pd(aryl)(alkyl) complexes. The experimental rates of this step correlate poorly with common parameters, such as the steric property or the electron-withdrawing ability of the fluoroalkyl ligand, making the prediction of rates and the rational design of Pdcatalyzed fluoroalkylations difficult. Therefore, a systematic study of the features of fluoroalkyl ligands that affect the barrier to this key step, including steric properties, electron-withdrawing properties, and secondary interactions, is necessary for the future development of fluoroalkylation reactions that occur under milder conditions and that tolerate additional types of fluoroalkyl reagents. We report computational studies of the effect of the fluoroalkyl (R F ) ligand on the barriers to reductive elimination from Pd(aryl)(R F ) complexes (R F = CF 2 CN, CF 2 C(O)Me, etc.) containing the bidentate ligand di-tert-butyl(2-methoxyphenyl)phosphine (L). The computed Gibbs free-energy barriers to reductive elimination from these complexes suggest that fluoroalkylarenes should form quickly at room temperature for the fluoroalkyl ligands we studied, excluding R F = CF 3 , CF 2 Me, C 2 F 5 , CF 2 CFMe 2 , CF 2 Et, CF 2 iPr, or CF 2 tBu. Analyses of the transition-state structures by natural bond orbital (NBO) and independent gradient model (IGMH) approaches reveal that orbital interactions between the Pd center and a hydrogen atom or π-acid bonded to the α-carbon atom of the R F ligand stabilize the lowest-energy transition states of Pd(aryl)(R F ) complexes. Comparisons between conformers of transition-state structures suggest that the magnitude of such stabilizations is 4.7− 9.9 kcal/mol. In the absence of these secondary orbital interactions, a more electron-withdrawing fluoroalkyl ligand leads to a higher barrier to reductive elimination than a less electron-withdrawing fluoroalkyl ligand. Computations on the reductive elimination from complexes containing para-substituted aryl groups on palladium reveal that the barriers to reductive elimination from complexes containing more electron-rich aryl ligands tend to be lower than those to reductive elimination from complexes containing less electron-rich aryl ligands when the fluoroalkyl ligands of these complexes can engage in secondary orbital interactions with the metal center. However, the computed barriers to reductive elimination do not depend on the electronic properties of the aryl ligand when the fluoroalkyl ligands do not engage in secondary orbital interactions with the metal center.

Copper-Mediated Cyanodifluoromethylation of (Hetero)aryl Iodides and Activated (Hetero)aryl Bromides with TMSCF2CN

“…Oxidative addition is computed to be rate-determining because the differences in energies between TS RE ‡ -a–c and [Cu]-3-a–c , respectively, are smaller than the differences between TS OA ‡ -a–c and [Cu]-3-a−c for each of the fluoroalkyl groups investigated. Our group has previously identified by computation a stabilizing interaction between the palladium center and the nitrile CN bond during reductive elimination from a phosphine-ligated fluoroalkyl–arylpalladium complex; however, we did not identify an analogous stabilizing interaction between the copper center and the nitrile CN bond in [Cu]-3-a−c using an independent gradient model based on Hirschfield partitions (IGMH analysis) …”

Insights into the mechanism and origin of multifunctional ligand effects on chemoselectivity in Pd-catalyzed unnatural prenylation and geranylation of oxindoles with isoprene

“…NPA analysis could also help evaluate intra- and intermolecular interactions and estimate the strength of the coordination interaction of the metal palladium and the ligand. 62 Herein, we carried out a second-order perturbation analysis of the NBOs on transition states TS1a , TS3a , and TS4a (Table S2†). In transition state TS4a , the sum E (2) values of d → n*, σ → d*, and n → d* interactions between Pd and CC (olefin) as well as the MeO − group is 127.6 kcal mol −1 , which is larger than d → π* of Pd⋯CC (olefin) in TS1a (24.4 kcal mol −1 ) and d → π*, σ → d*, and n → d* in TS3a (71.6 kcal mol −1 ).…”

“…This variation further confirmed that the coordination environment of the metal center changes from the Pd-P double coordination model to NPA analysis could also help evaluate intra-and intermolecular interactions and estimate the strength of the coordination interaction of the metal palladium and the ligand. 62 Herein, we carried out a second-order perturbation analysis of the NBOs on transition states TS1a, TS3a, and TS4a (Table S2 † Moreover, the substrate oxindole provides the n → σ* interaction between O1 and H2 to stabilize the TS4a structure, which is absent in TS1a and TS3a. Therefore, the cooperative action of the phosphine ligand, the double bond on the substrate isoprene, MeOH, and the palladium catalyst were found to be crucial for the preferential ΔG ‡ value of TS4a.…”