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 Pd-catalyzed 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 $\left({\text{R}}^{\text{F}}\right)$ ligand on the barriers to reductive elimination from $\text{Pd}\left(\text{aryl}\right)\left({\text{R}}^{\text{F}}\right)$ complexes ( ${\text{R}}^{\text{F}}={\text{CF}}_2\text{CN}$ , ${\text{CF}}_2\text{C}\left(\text{O}\right)\text{Me}$ , 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 ${\text{R}}^{\text{F}}={\text{CF}}_3$ , ${\text{CF}}_2\text{Me}$ , ${\text{C}}_2{\text{F}}_5$ , ${\text{CF}}_2{\text{CFMe}}_2$ , ${\text{CF}}_2\text{Et}$ , ${\text{CF}}_{2}i\text{Pr}$ , or ${\text{CF}}_{2}t\text{Bu}$ . 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 $\pi$ -acid bonded to the $\alpha$ -carbon atom of the ${\text{R}}^{\text{F}}$ ligand stabilize the lowest-energy transition states of $\text{Pd}\left(\text{aryl}\right)\left({\text{R}}^{\text{F}}\right)$ complexes. Comparisons between conformers of transition-state structures suggest that the magnitude of such stabilizations is 4.7-9.9kcal/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.

Keywords: DFT calculations; fluoroalkylation; palladium catalysis; reductive elimination; secondary orbital interactions.

Figure 1.

Comparison of experimentally determined and computed barriers to reductive elimination from (a) (dfmpe)Pd(Ph)(CF3), (b) ((S)-SEGPHOS)Pd(4-CN-C₆H₄)(fluorooxindole), (c) (dppf)Pd(Ph)(CF₂CN), and (d) (dppf)Pd(Ph)(CF₂CO₂Et).

Figure 2.

Optimized structures and selected geometric parameters of (a) cis-Pd-CF₂Ph-GS, (b) cis-Pd-CF₂Ph-TS, (c) rans-Pd-CF₂Ph-GS, and (d) trans-Pd-CF₂Ph-TS. Hydrogen atoms have been omitted for clarity.

Figure 3.

Linear relationship between the Q(CF₂X) and the ${\sigma }_m\left(\text{X}\right)$ values for a series of difluoroalkyl ligands.

Figure 4.

Plots of computed barriers to reductive elimination $({\Delta \text{G}}^{‡}\left({\text{R}}^{\text{F}}\right))$ against $\text{Q}\left({\text{R}}^{\text{F}}\right)$ values (a) without partitioning of R^F ligands into subsets and (b) with partitioning of R^F ligands into subsets.

Figure 5.

NBO and IGMH analyses of the stabilizing secondary orbital interactions in cis-Pd-R^F-TS structures between the Pd center and (a) the $\alpha$-carbonyl group for ${\text{R}}^{\text{F}}={\text{CF}}_2\text{C}\left(\text{O}\right)\text{Me}$, (b) the $\alpha$-nitrile group for ${\text{R}}^{\text{F}}={\text{CF}}_2\text{CN}$, and (c) the $\alpha$-phenyl group for ${\text{R}}^{\text{F}}={\text{CF}}_2\text{Ph}$. NBO isosurfaces depict the leading orbitals involved in the $d\left(\text{Pd}\right)\to {\pi }^{\text{*}}\left({\text{R}}^{\text{F}}\right)$ interactions. Blue isosurfaces labeled with black arrows in the IGMH plots indicate stabilizing interactions between the R^F ligand and the Pd center.

Figure 6.

NBO and IGMH analyses of the stabilizing secondary orbital interactions between the Pd center and the $\text{C}\left(\alpha \right)-\text{H}$ bond in the transition state cis-Pd-CF₂H-TS. (a) Visualization of the $d\left(\text{Pd}\right)\to {\sigma }^{\text{*}}\left(\text{C}-\text{H}\right)$ orbital interaction. (b) Visualization of the $\sigma \left(\text{C}-\text{H}\right)\to s\left(\text{Pd}\right)$ orbital interaction. (c and d) IGMH plots; blue isosurfaces labeled with black arrows indicate stabilizing interactions between the R^F ligand and the Pd center.

Figure 7.

(a) Wiberg bond index between Pd and CN along the reaction coordinate for the reductive elimination from the cis-Pd-CF₂CN complex. (b) Wiberg bond index between Pd and $\alpha$-H along the reaction coordinate for the reductive elimination from the cis-Pd-CF₂H complex. (c) Rationalizations for why secondary orbital interactions are specific to the transition states.

Figure 8.

Optimized transition-state structures of (a) cis-Pd-CF₂C(O)Me-TS, (b) cis-Pd-CF₂C(O)Me-TS-rot, (c) cis-Pd-CF₂H-TS, and (d) cis-Pd-CF₂H-TS-rot.

Figure 9.

Linear correlation between $\Delta G_{\text{no-orb}}^{‡}\left({\text{R}}^{\text{F}}\right)$ and $\text{Q}\left({\text{R}}^{\text{F}}\right)$. $\Delta G_{\text{no-orb}}^{‡}\left({\text{R}}^{\text{F}}\right)$ is the estimated hypothetical barrier to reductive elimination through the lowest-energy transition-state structure cis-Pd-R^F-TS in the absence of secondary orbital interactions between the Pd center and the R^F ligand; “no-orb” stands for “no orbital”.

Scheme 1

Scheme 2.

Reported Pd-Catalyzed Aryldifluoromethylation of Aryl Halides and the Model System Studied in This Work

Scheme 3.

Illustration of the Definition of $Q\left(R^F\right)$ Using R^F = CF₂CN as an Example^{a a}Q(CF₂CN) is equal to the sum of the QTAIM partial charge of each atom of the CF₂CN fragment in the lowest-energy ground-state structure cis-Pd-CF₂CN-GS.