Computational Studies of Heteroatom‐Assisted CH Activation at Ru, Rh, Ir, and Pd as a Basis for Heterocycle Synthesis and Derivatization

Abstract

IntroductionModern computational chemistry is a key tool by which insight into organometallic reaction mechanisms can be gained. The ability to characterize short-lived intermediates and transition states provides an ideal complement to experiment, where such information is often extremely difficult, if not impossible, to obtain. Recent years have seen great advances in understanding the mechanisms of C-H bond activation, and this area was the subject of several major reviews toward the end of the last decade [1,2]. More recently, the focus has shifted to how C-H activation can be integrated into catalytic cycles for useful organic transformations. The C-H bond activation event is itself mechanistically diverse, with oxidative addition (OA), σ-bond metathesis (SBM), and electrophilic activation (EA) all potentially available at late transition metal centers, depending on the metal, its oxidation state, and the coordination environment. C-H activation assisted by a heteroatom base (typically a carboxylate or carbonate) falls into the last of these categories and forms the focus of this chapter. More recently, computational studies of catalytic cycles for C-H activation and functionalization have become more common. These reveal the complexity of what are usually multiple-step processes, and calculations are particularly well placed to test different mechanistic possibilities. Such studies are most effectively pursued through a close interaction between experiment and computation, and increasingly this is allowing for a more quantitative assessment of computed reaction mechanisms.As well as progress in mechanistic understanding, the last 10 years have seen important developments in the computational methodologies available to model transition metal reactivity. While density functional theory (DFT) remains the core method of choice, the ability to model larger systems that more closely reflect experiment has highlighted the known shortcomings of DFT in describing dispersion interactions. These long-range, stabilizing interactions are individually weak, but their cumulative effect in large systems can be significant. Methods to incorporate this component include its separate calculation (e.g., Transition Metal-Catalyzed Heterocycle Synthesis via C-H Activation, First Edition. Edited by Xiao-Feng Wu.

Computational Studies of Carboxylate-Assisted C–H Activation and Functionalization at Group 8–10 Transition Metal Centers

“…A brief overview of computational work prior to 2010 will be given to provide appropriate context. Some aspects of this Review have been summarized elsewhere, but are included here for completeness. , …”

“…Energies are in kcal/mol and include a correction for zero-point energies; selected distances are in angstroms . Adapted with permission from ref . Copyright 2016 John Wiley and Sons.…”

Transition-Metal-Mediated Nucleophilic Aromatic Substitution with Acids

“…In contrast to the current approach involving direct attack by an external nucleophile (referred herein as E-S N Ar), ,, we envisioned another mechanism where the attacking nucleophile is within the metal coordination sphere prior to S N Ar (I-S N Ar, Scheme ). The latter involves a formal migratory insertion step but contains elements similar to a C–H bond activation mechanism known as concerted metalation–deprotonation (CMD), wherein coordinated nucleophiles can deprotonate C–H bonds. The analogous I-S N Ar mechanism should operate equally well with protic and poorly nucleophilic AcOH and HTFA, avoiding the prototypical protic solvent inhibition.…”

Simulated Mechanism for Palladium-Catalyzed, Directed γ-Arylation of Piperidine

“…Prior quantum chemical studies on transition-metal-catalyzed reactions involving C–H activation ,− , have used DFT to explain observed site selectivity, − understand the C–H activation mechanism, − and determine the role of the directing group, − catalyst, − ,, additives, − or oxidants − in the catalytic cycle. Notably, studies by several research groups ,,− ,,,, have shown Pd carboxylate catalysts, such as Pd acetate (Pd­(OAc) 2 ), facilitate C–H activation using the carboxylate base as the proton acceptor.…”

“…Our computational studies have examined the catalytic cycle shown in Scheme , which involves six main steps. , These steps are (1) generation of the active catalyst through bidentate chelation of the substrate to Pd, which also orients the Pd center near the γ-carbon, (2) C–H activation of the γ-carbon after piperidine undergoes a chair to boat conformational switch, (3) oxidative addition of ArI across the Pd­(II) center, generating a high-valent Pd­(IV) species, (4) reductive elimination of the arylated product, (5) iodine abstraction from Pd by CsOAc, and (6) product dissociation and chelation of a new substrate at the Pd center to regenerate the active catalyst.…”