Density Functional Theory Investigation of the Alkyl–Alkyl Negishi Cross‐Coupling Reaction Catalyzed by N‐Heterocyclic Carbene (NHC)–Pd Complexes

Abstract

A novel mechanism is proposed for the Pd-1,3-(2,6-diisopropylphenyl)imidazolyl-2-ylidene (1) catalyzed Negishi reaction. DFT computations supported by atoms-in-molecules (AIM) analyses of non-truncated models show that a "steric wall" created by the N-substituent on the ligand guides reactants to and from the Pd center. Notably, transmetalation and not oxidative addition is found to be rate-limiting. Additionally, a key Pd-Zn interaction (approximately = 2.4 A, rho(b) approximately = 0.0600 au) is identified in the mechanism. This interaction persists beyond reductive elimination and, in combination with the ligand, facilitates reductive elimination by creating a highly sterically crowded environment in the coordination sphere of the Pd center.

Structure–Activity Relationship Analysis of Pd–PEPPSI Complexes in Cross‐Couplings: A Close Inspection of the Catalytic Cycle and the Precatalyst Activation Model

“…Unexpectedly, complexes that had previously proven inactive (9)(10)(11)(12)(13)(14) were able to generate significant cross-coupled product, which perhaps indicates that something unique occurs with aryl organozinc reagents.…”

“…[11,12] have revealed that these species are completely inactive in Negishi reactions and that the active catalyst must therefore be a palladium complex with only one NHC ligand. [9,13,14] With the uncertainty of the in situ protocol in mind, our group [12,15] and others [7,16] embarked on the development of well-defined NHC-Pd precatalysts (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

“…Of these four complexes (1,7,10,11), two have sterically encumbered isopropyl groups at the ortho positions of the N-phenyl substituent (i.e., 1 and 7) and these have proven to be highly reactive in SuzukiMiyaura, [12,17] Negishi, [15] and Kumada-Tamao-Corriu (KTC) [18] cross-couplings, and Buchwald-Hartwig-Yagu-A C H T U N G T R E N N U N G polskii amination. [19] We have been studying the origin of the reactivity of these NHC-based catalysts by using a variety of techniques, including computation [14] and NMR spectroscopy, [20] and all analyses indicate that increasing bulk at the ortho position of N-phenyl NHCs should lead to an in-crease in reactivity. Of course, catalyst activation is another very important aspect of overall catalyst reactivity; similarly to the in situ-derived catalysts, if the active reduced catalyst does not form, turnover is not possible.…”

“…These results support the idea that more s-donating ligands on palladium facilitate oxidative addition, [22] and promote complex stability (no blacking-out of Pd 0 was observed), whereas the more sterically bulky ligands facilitate reductive elimination (or transmetalation). [12,14,23] However, there appears to be a limit to the amount of bulk tolerated because the bulkier adamantyl groups (14) form an altogether different topography around the metal that may cause them to be virtually ineffective as cross-coupling catalysts (see Figure 3).…”

“…However, the different steric topography that they impart around the palladium centre would have a greater impact on the rate of transmetalation and/or reductive elimination. [14] We have been studying the relationship between sterics and electronics brought about by the N substituents on the NHC by examining the 109 Ag NMR carbene chemical shifts of analogous NHC-Ag complexes. With increasing steric bulk on the NHC, the carbene chemical shifts were observed to be more downfield, which suggests a more electron-deficient metal centre.…”