Chapter 1
Computational Studies of Heteroatom-Assisted C-H Activation at Ru, Rh, Ir, and Pd as a Basis for Heterocycle Synthesis and Derivatization

Kevin J. T. Carr, Stuart A. Macgregor and Claire L. McMullin

1.1 Introduction

Modern 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), s-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., with Grimme's D3 parameter set [3]), use of functionals that include a treatment of dispersion (e.g., B97-D [4], ?B97X-D [5]), or use of a Minnesota functional (e.g., M06 or its variants [6]) where the functional parameterization (e.g., to reproduce molecular structures from crystallographic data) captures dispersion effects without explicitly identifying them. The validity of such approaches is seen, for example, in marked improvements in calculated LnM-PR3 dissociation energies [7]. These developments make the choice of functional for the study of C-H activation and functionalization especially critical when larger models are employed in calculations.1

This chapter will focus on how computational chemistry has provided insights into heteroatom-assisted C-H activation and functionalization at Ru, Rh, Ir, and Pd metal centers. These will include reactions that both construct new heterocycles and those that introduce new substituents into an already intact heterocyclic skeleton. The text will first cover Pd and will then treat Ru, Rh, and Ir together, providing in each case a brief background on computational work on heteroatom-assisted C-H activation. More recent developments will then be considered covering the literature since our last review [1b], that is, from 2009 until March 2015. In many cases, work on nonheterocyclic substrates is included to illustrate important general points regarding the C-H activation mechanism. Unless otherwise stated, DFT calculations have been employed throughout and only the major functional employed in each study will be highlighted, along with any solvent used in brackets. The notation DFT2//DFT1 will be used to indicate cases where a second functional (DFT2) has been used to recompute the energy of a system optimized with an initial functional (DFT1). The original papers should be consulted for full computational details.

1.2 Palladium

1.2.1 Intramolecular Heteroatom-Assisted C-H Activation

1.2.1.1 Early Computational Studies

Computational work under this heading stems from 2005 when Davies, Macgregor, and coworkers reported BP86 calculations on the cyclometalation of dimethylbenzylamine at Pd(OAc)2 [8], a system that had been the subject of detailed experimental studies in the 1980s by Ryabov and coworkers (Figure 1.1) [9]. Starting from Pd(OAc)2(Me2NCH2Ph), 1, a two-step process was characterized involving initial displacement of one arm of the ?2-OAc ligand by the incoming ortho-C-H bond of the benzyl substituent. This forms an agostic intermediate, 2, that polarizes the C-H bond and sets up an H-bond to the pendant arm of the OAc ligand. C-H cleavage then proceeds with a minimal barrier to give the cyclometalated product, 3, as an HOAc adduct. The overall barrier was computed to be 13 kcal mol-1 with the initial ?2-?1 displacement of acetate via TS(1-2) corresponding to the highest point on the profile. Alternative mechanisms including oxidative addition or proton transfer onto the Pd-bound acetate oxygen were found to entail considerably higher barriers. The implication of an agostic intermediate, as opposed to a Wheland (or arenium)-type species, was significant as it indicates a fundamental difference to electrophilic aromatic substitution (SEAr) processes. This type of reaction was subsequently characterized as proceeding via "ambiphilic metal-ligand assistance" (AMLA), a term that stresses the synergic role of the electron-deficient metal center and the nearby intramolecular base in promoting facile C-H bond activation [1b]. Both AMLA-6 and AMLA-4 processes have been defined, depending on whether a six-membered or four-membered transition state is involved. The role of an agostic intermediate indicates AMLA C-H activation is not (unlike SEAr) restricted to aromatic C-H bonds, and indeed the equivalent C(sp3)-H activation of Me2NCH2CH2CH3 was predicted to proceed with a barrier of only 20 kcal mol-1.

Figure 1.1 Computed reaction profile for C-H activation in Pd(OAc)2(Me2NCH2Ph). Energies are in kcal/mol and include a correction for zero-point energies; selected distances in Å [8].

Shortly afterward, Maseras, Echavarren, and coworkers published a B3LYP study on C-H activation in Pd(2-phenethylphenyl)(X)(PH3) species (4, X = Br or HCO3, Figure 1.2), as model intermediates in Pd(OAc)2-catalyzed intramolecular C-C coupling [11]. The Pd-aryl bond is formed via oxidative addition of an aryl bromide precursor and acts as a directing group. With X = HCO3, C-H activation proceeds by a one-step proton abstraction via TS4A in a similar way to that seen at Pd(OAc)2(Me2NCH2Ph), albeit without an agostic intermediate being located. With X = Br, proton abstraction was much less accessible; however, in this case, external deprotonation by a bicarbonate anion (TS4B) was found to be competitive. A follow-on study showed that both intra- and intermolecular deprotonation mechanisms correctly capture the accelerating effect of electron-withdrawing substituents (F, Cl) on the aryl ring, as seen experimentally [10]. Such patterns are again inconsistent with a SEAr mechanism.

Figure 1.2 C-H activation transition states derived from 4, involving internal (TS4A) and external (TS4B) deprotonation. Computed free energies in kcal mol-1 and key distances in Å [10].

The importance of agostic interactions was also seen in the ability to cleave C(sp3)-H bonds as part of the Pd-catalyzed synthesis of dihydrobenzofurans (5 6, Figure 1.3a) reported by Fagnou and coworkers [12]. B3LYP calculations on a model Pd(Ar)(OAc)(PMe3) species, 7, characterized a series of concerted, inner-sphere deprotonation mechanisms for reaction at the three distinct C(sp3)-H bonds of the 2-methylbutoxy substituent (Figure 1.3b). Reaction at one of the Me positions that results in a six-membered palladacycle is favored via TS7A over activation of either the CH2 or CH3 groups of the ethyl substituent via TS7B and TS7C, respectively, the latter forming a seven-membered palladacycle. These one-step C-H activation processes were consistent with the "concerted metalation deprotonation" (CMD) concept that Fagnou and coworkers were developing at this time. Lledós and Urriolabeitia found similar B3LYP-computed processes accounted for observed selectivities in the cyclometalation of stabilized iminophosphoranes, Ar3P=NC(O)Ph at Pd(OAc)2, where exo activation via an agostic intermediate is kinetically favored over a one-step endo activation [13].

Figure 1.3 (a) Pd-catalyzed formation of dihydrobenzofurans and (b) alternative transition states for C(sp3)-H activation with computed free energies relative to Pd(Ar)(OAc)(PMe3), 7, in kcal mol-1 [12].

Overall, these early studies of...