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Computational Studies of Synthetically Relevant Homogeneous Organometallic Catalysis Involving Ni, Pd, Ir, and Rh: An Overview of Commonly Employed DFT Methods and Mechanistic Insights Theresa Sperger,† Italo A. Sanhueza,†,‡ Indrek Kalvet,† and Franziska Schoenebeck*,† †

Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany Laboratory of Organic Chemistry, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland

‡

5.2. Olefin Functionalization 5.2.1. Hydroformylation 5.2.2. Hydroacylation 5.2.3. Hydroaminomethylation 5.2.4. Hydroamination 5.2.5. Hydrosilylation 5.2.6. Hydroboration 5.3. Conjugate Addition 5.4. C−H Activation and Other Bond Activations 5.4.1. C−H Activation 5.4.2. C−F Activation 5.4.3. C−CN Activation 5.4.4. C−O and O−O Activation 5.4.5. N−H Activation 5.5. Reactions of Rh Carbenoids and Nitrenoids 5.5.1. Rh Carbenoids 5.5.2. Rh Nitrenoids 5.6. Cyclization Reactions 5.6.1. [5 + 2] and [6 + 2] Cycloadditions 5.6.2. [3 + 2] Cycloadditions 5.6.3. [3 + 2 + 2] and [2 + 2 + 2] Cyclizations 5.6.4. [4 + 1] Cycloadditions 5.6.5. Ring-Opening Reactions 6. Iridium 6.1. Hydrogenation 6.1.1. Classical Hydrogenation 6.1.2. Transfer Hydrogenation 6.1.3. Dehydrogenation 6.2. Olefin Functionalization 6.2.1. Hydroamination 6.3. Allylic Substitution 6.4. C−H Bond Activation and Other Bond Activations 6.4.1. C−H Activation 6.4.2. C−F Activation 6.4.3. C−O Activation 6.4.4. Borylation 6.5. Reactions of Ir Carbenoids 6.6. Cyclization Reactions 7. Conclusion and Outlook Author Information Corresponding Author Notes

CONTENTS 1. Introduction 2. Computational Methodology 2.1. Geometry Optimizations 2.2. Energy 3. Palladium 3.1. Coupling Reactions 3.1.1. Oxidative Addition 3.1.2. Reductive Elimination 3.1.3. Suzuki−Miyaura Coupling 3.1.4. Stille Coupling 3.1.5. Hiyama Coupling 3.1.6. Negishi Coupling 3.1.7. Heck Coupling 3.1.8. Sonogashira Cross-Coupling 3.2. Aryl Trifluoromethylation 3.3. C−H Bond Activation 3.4. Allylic Substitution 3.5. Cyclization Reactions 4. Nickel 4.1. Coupling Reactions 4.1.1. Oxidative Addition 4.1.2. Suzuki Coupling 4.1.3. Kumada Coupling 4.1.4. Negishi Coupling 4.1.5. Heck Coupling 4.1.6. Alkyne−Aldehyde Coupling 4.2. C−H Bond Activation 4.3. C−O Bond Activation 4.4. Cyclization Reactions 4.5. Olefin Functionalization 5. Rhodium 5.1. Hydrogenation 5.1.1. Classical Hydrogenation 5.1.2. Transfer Hydrogenation © XXXX American Chemical Society

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Special Issue: 2015 Frontiers in Organic Synthesis Received: March 17, 2015

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DOI: 10.1021/acs.chemrev.5b00163 Chem. Rev. XXXX, XXX, XXX−XXX

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Ir-catalyzed transformations, (ii) the choice and performance (when possible) of computational methodology used therein, and (iii) the numerous mechanistic insights gained. We hope that this review will stimulate further implementation of computational tools in mechanistic studies and inspire innovative theoretical developments for the study of organometallic transformations.

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1. INTRODUCTION The field of organometallic catalysis has attracted considerable interest from both academia and industry due to its broad applications in synthetic transformations. Pd, Ni, Rh, and Ir catalysts are critical for many of these transformations, often giving rise to remarkable reactivities that were unthinkable in the past.1 Owing to the tremendous advances in computational methodology, computing power and software, computational tools are increasingly employed to study, rationalize, and predict organometallic reactivities. Computational chemistry has in particular become a powerful tool to gain insights into the mechanisms of catalytic organometallic processes where the active catalytic species or intermediates have been challenging or impractical to study via experimental approaches.2 However, there are also numerous challenges associated with the mechanistic studies of catalytic transformations. These are not only due to the limits in accuracy of the employed computational methodology but also due to the inherent complex nature of catalytic cycles that frequently involve numerous intermediates and mechanistic possibilities. In addition, the conformational freedom of commonly employed organometallic complexes and ligands and the precise reproduction of conditions (solvent and additive effects) constitute additional challenges.2 Nevertheless, when teamed up with experimental studies or if used to address specific relative trends in reactivities, the employment of computational tools will undoubtedly offer deeper insights than any other currently available approach.2 Several reviews and book chapters have dealt with different aspects of computational chemistry,3−14 including the underlying theory and methodology of computational chemistry,15−20 as well as its applications in areas such as organic reactivity,21−24 selectivity,25,26 and NMR calculations.27,28 In addition, several reviews covering transition metals have been reported,1,29−32 including that from our own group which reviews the combined computational and experimental studies of palladium in a variety of oxidation states.33 However, to the best of our knowledge, computational studies of synthetically relevant transformations enabled by Ni, Ir, or Rh have so far not been reviewed extensively.34−37 Herein, we aim to present a review on computational studies of Pd-, Ni-, Rh-, and Ir-mediated transformations that have been conducted between 2008 and 2014 and been of significance for organic synthesis.38 For clarity, this review has been divided into four sections (one for each metal) in which the computational studies are arranged according to specific reaction categories. In addition, a section on commonly employed computational methodology is presented. For the latter, it was not intended to present an exhaustive theoretical background but rather to provide a statistical overview (based on all publications referenced in the Pd, Ni, Rh, and Ir sections) of commonly employed methodology (i.e., Density Functional Theory (DFT)39,40) and on reviewing benchmark studies that address the computational performance in geometry and energy calculations of Pd-, Ni-, Rh-, and Irmediated reactions. Overall, this review is meant to provide the reader with a summary of (i) the recent computational studies that have been conducted in relation to synthetically relevant Pd-, Ni-, Rh-, and

2. COMPUTATIONAL METHODOLOGY The current computational studies of organometallic (and also organic) systems are frequently subjected to a compromise of accuracy and time: while it is always desired to reach the highest possible accuracy in the computational assessment, the necessity to complete the calculations within a reasonable time scale does not always allow for that.41 For example, coupled cluster (CC) methods like CCSD(T)42,43 are generally considered to be the gold standard in modern quantum chemistry but are often impractical or impossible to apply for calculations involving chemically relevant (and generally large) Pd, Ni, Rh, and Ir complexes, particularly for the optimization of geometries.44 Thus, for reactions involving these organometallic species, DFT has generally been the method of choice and shown to give an adequate compromise between computational speed and accuracy.16,20,45−47 2.1. Geometry Optimizations

In order to obtain reliable chemical information from calculations, accurate molecular geometries are essential since they are the basis for other calculations, such as property and energy calculations.48−51 In the context of DFT, decades of research have provided the scientific community with a variety of methods (Table 1). Table 1. Overview of Popular DFT Methods GGA

metaGGA

hybrid-metaGGA

BP8652−54 B97D55

M06L56 TPSS57

M0658 M062X58

hybrid-GGA B3LYP53,59,60 B3PW9153 PBE061

range separated ωB97X-D62 DFT-D363

However, as stated in a study by Martin and co-workers,64 there is currently no universal method for calculations on Pd, Ni, Rh, and Ir (and related) species. Instead, there is a group of methods (especially hybrid ones) that dominates the field of organometallic Pd, Ni, Rh, and Ir calculations. The statistical data in Figure 1 summarize the 10 most popular DFT methods employed in the Pd, Ni, Rh, and Ir sections and suggest that currently, similar to the period of 2008−2009, B3LYP is still the first choice for geometry optimization of Pd, Ni, Ir, and Rh species.65 However, with the increased availability of other methods, such as ωB97X-D and the Minnesota functionals, the dominance of B3LYP appears to be fading. [It has to be stated in this context that the apparent “popularity” of a method may also be biased by its availability in the commonly used software packages.] In contrast, the choice of basis set and effective core potential (ECP) for geometry optimization has not changed significantly during the past eight years (Figure 1c and 1d). The calculations discussed and referenced in this review indicate that the calculations are still dominated by LANL2DZ67−69 as ECP for the transition metal, typically being combined with a Pople basis set (e.g., 6-31G(d) or 6-31G(d,p)) for main-group atoms. The B


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Figure 1. Distribution of DFT methods (a and b) and basis sets (c and d) employed in 2008−2009 and 2013−2014 for geometry optimization. Data are based on all reviewed computational studies included in the following Pd, Ni, Rh, and Ir sections. Only the 10 most popular methods and 5 most popular basis sets (employed in the computational studies reviewed herein) are accounted for.66

Stuttgart-Dresden70 (SDD) ECP with or without polarization functions is also frequently employed as it offers more flexibility (than LANL2DZ) in the valence shell.71 The extensive usage of B3LYP is likely related to its proven overall good accuracy for a wide range of systems.72−74 For instance, in a study on Pd-catalyzed allylic fluorination, Doyle, Norrby, and co-workers showed that B3LYP could reproduce allylic Pd(II) chloride X-ray structures within 5% error (Figure 2a).75 Also, in a study by Pratt et al., the authors observed that,

B3LYP may perform well in reproducing experimental X-ray data of alkene−Ir(Cp) complexes (Figure 2c).77 Besides B3LYP, other popular methods such as BP86, B3PW91, and PBE0 have also shown acceptable and sometimes even better performance than B3LYP in reproducing crystallographic structural data of organometallic complexes.74,78 This was also the case in a benchmark study by Bühl and co-workers in which, relative to experimental gas-phase electron diffraction, it was shown that, e.g., B3PW91 can have an overall better performance than B3LYP in the structure optimization of several second-row transition-metal complexes, such as Rh(NO)(PF3)3 and RhCp(C2H4)2 (Figure 2d).79 In a related benchmark study, Bühl and co-workers showed that for Ir (and related third-row transition-metal complexes) the DFT methods PBE0, B3P86,54,59 and B3PW91 can perform better than B3LYP in reproducing experimental structural data (obtained from gas-phase diffraction or microwave spectroscopy).78 Moreover, with respect to the ECP, the authors in this study recommended the use of SDD for the general geometry optimization of molecules involving transition metals. However, given that B3LYP and other popular methods, mentioned above, are limited by the fact that they do not account well for dispersion interactions,80 their usage may not always be the best choice for geometry optimization of Pd, Ni, Ir, and Rh catalysts. Instead, the choice of method is entirely system

Figure 2. Examples of transition-metal complexes where accurate geometries may be obtained when employing the popular density DFT methods, such as B3LYP or other “dispersion-free” methods.75−77,79

relative to CCSD(T) reference data, B3LYP performed well and could successfully be employed for geometry optimization of reactants and intermediates in an alkyl coupling reaction with a small Ni complex (Figure 2b).76 Similar conclusions were also obtained in a study by Hughes and co-workers who observed that C


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homogeneous catalysis, intramolecular dispersion forces in the catalyst may be negligible, and its incorporation in the geometry optimization might lead to artificial intramolecular interactions that do not necessarily exist in solution.

dependent, i.e., depends on the nature and degree of intramolecular interactions in the structure. A related example on Ru (although not a transition metal covered in this review, but similar) is the study by Calhorda et al. in which the geometry optimization performance of several pure or hybrid methods, to reproduce the structure of a cationic Cp− Ru−allyl complex, was evaluated relative to experimental X-ray data (Figure 3).81 The authors observed that particularly the

2.2. Energy

Energy calculations are also important steps for accurate and reliable studies of Pd, Ni, Rh, and Ir complexes and related systems.49 In particular, reaction energies and activation barriers are of great importance since they provide the basis for qualitative/quantitative mechanistic analysis of different organometallic reactions and for the development of organometallic reactivity. Unfortunately, since the coverage of benchmark studies that deal with the accuracy of organometallic energy calculations is rather limited or covers only relatively small systems, the choice of method is not always trivial. This is, in particular, the case for the transition metals reviewed herein, which to our knowledge have been covered to a limited extent in benchmark studies. The reasons for this are likely due to (1) the size of commonly employed Pd, Ni, Rh, and Ir catalysts, which makes CCSD(T) reference data very difficult to obtain, and (2) the limited amount of reliable experimental data that can be employed as reference data in computational benchmark studies. Consequently, there is an inherit risk of possibly choosing the wrong computational method for Pd-, Ni-, Rh-, and Ir-mediated reactions. A close link to experiments is therefore advisable.2,14 With respect to the popularity of different DFT methods, the statistical data in Figure 5 shows that for energy calculations the dominance of B3LYP has been fading during the past eight years and is, in many cases, being replaced by dispersion-corrected methods, such as the Minnesota functionals or DFT-D3, as they have been shown to perform better in reproducing important chemical parameters such as activation barriers and reaction energies.16,44,58,85−87 Currently, the first choice for energy calculations is M06, followed by B3LYP, DFT-D3, and M06L, whereas the choice of basis set for the description of the transition metal is dominated by SDD, followed by LANL2DZ. In the context of the performance of DFT methods and energy calculations, depending on the organometallic system, methods that do not include dispersion may in certain cases still be a valid choice. For instance, in a study by Grimme and co-workers the dispersion-free BP86 method performed relatively well in predicting the experimental dissociation enthalpies of four small 3d transition metals. Among these results, BP86 calculations on Ni(CO)4 predicted a respectable dissociation enthalpy of 26.7 kcal/mol, which was only 1.7 kcal/mol off from the experimental results (25 kcal/mol).89 Also, recently H. Chen and co-workers benchmarked the C−H activation of a small methane molecule by Pd, Ir, and Rh pincer complexes that employed several different pincer ligands. On the basis of LCCSD(T)90 reference data, the benchmark study showed that for the C−H activation step, in terms of mean unsigned deviation (MUD), B3LYP (MUD = 1.17) was the most accurate DFT method followed by B2GPLYP (MUD = 2.20),91 B2PLYP (MUD = 2.26),92 and PBE0 (MUD = 2.27).93 Nonetheless, given that many Pd-, Ni-, Rh-, and Ir-mediated transformations involve bimolecular processes and bear large ligands, the quantitative and qualitative accuracy of energy calculations has in many cases been greatly influenced by dispersive effects.16,37,58,85,94−98 For instance, Truhlar and coworkers evaluated the performance of several DFT methods to describe the binding energy of several alkenes (CnHn+2 for n = 2, 6, 10) to Pd(PH3)2.99 Figure 6 displays an extract of the

Figure 3. Calculations on a cationic Ru complex by Calhorda, Jacobsen, and Grimme.81−83 Ru−C3 distance is reported in Angstroms. Distance errors, relative to experimental results, are in parentheses.

C3−Ru distance was substantially overestimated by many of the tested DFT methods. For instance, at the PBE/4-31G(d) (SDD +f for Ru) level of theory the distance was overestimated by 0.3 Å, whereas at the B3LYP/4-31G(d) (SDD+f for Ru) level of theory the distance was overestimated by 0.4 Å. This substantial error was initially presumed to be due to a possible failure of DFT to calculate transition-metal (TM) geometries. However, more recent calculations by Jacobsen in 201182 and Grimme in 201383 on the same complex showed that this was not necessarily a failure of DFT but instead related to crystal packing, counterions, and improper theoretical treatment of dispersion in “standard” DFT methods. As shown in Figure 3, the reoptimization by Jacobsen using dispersion-corrected BP86 (BP86-D255) with a triple-ζ basis set substantially lowered the error to about 0.10 Å which, by Grimme, was even further lowered to about 0.02 Å using periodic83 PBE-D3/def2-TZVP calculations. Similar results were observed in the benchmark study by Jensen and co-workers, who evaluated the optimization performance of several DFT methods to describe relatively large organometallic complexes (examples are shown in Figure 4).46

Figure 4. Examples of some transition-metal complexes that were evaluated by Jensen and co-workers. The study also included Ti, Fe, Co, Zr, Mo, and W complexes.46

In this study, the organometallic complexes were either catalyst precursors or important intermediates in the catalytic processes, and by comparing the computational results with crystallographic data the authors observed that the DFT method that gave the best overall geometry optimization performance (with respect to statistical errors) was the dispersion-corrected DFT method ωB97X-D, whereas B3LYP was attributed with large statistical errors. However, as discussed in a study by Jacobsen and Cavallo,84 one should not forget that dispersive interactions are often different in X-ray structures than in solution. Thus, for D


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Figure 5. Distribution of DFT methods (a and b) and basis sets (c and d) employed in 2008−2009 and 2013−2014 for energy calculations. Data are based on all reviewed computational studies included in the following Pd, Ni, Rh, and Ir sections. The six most popular DFT methods and eight most popular basis sets (employed in the computational studies reviewed herein) are accounted for.88

Figure 6. Calculated MUD binding energies (in kcal/mol) of CnHn+2 (n = 2, 6, 10) employing various DFT methods.99 Figure 7. Experimental and calculated free energy of reaction (kcal/ mol) for different density methods for oxidative addition of ammonia to Ir.101

benchmark results which shows that relative to wave function theory (WFT) calculations, the best performance (in terms of MUD) is observed for DFT methods that account for dispersion. More specifically, the overall best performance was observed when employing M06 with empirically damped dispersion correction27 (i.e., M06-D), followed by M06L-D, B97D, and ωB97X-D. Respectable results were also observed for M06L and M06. The latter has also shown good performance in calculating activation barriers of Ni- and Pd-mediated C−C bond activation of ethane100 and many other reactions discussed later in this review. In a similar context, Averkiev and Truhlar investigated the oxidative addition of ammonia to an iridium PCP pincer complex (Figure 7).101 Several DFT methods, such as B3LYP, PBE, ωB97X-D, CAM-B3LYP,102 M05,103 M06L, and M06 were evaluated against the experimental free energy of reaction, as reported by Hartwig and co-workers in 2005.104 Best performance to describe the free energy of the reaction was observed for

M06L, whereas methods such as ωB97X-D, B3LYP, and CAMB3LYP performed poorly. With respect to bond activation, Grimme and co-workers recently evaluated the performance of 23 DFT methods (e.g., PBE0-D3, B3LYP-D3, M06, and M062X) to describe four small neutral and anionic catalysts (Pd, PdCl−, PdCl2, and Ni) bond activations of C−H, C−C, O−H, B−H, N−H, and C−Cl bonds.105 The DFT methods were evaluated against CCSD(T) reference data, considering the reactant complexes, activation barriers, as well as the reaction energies. The best method relative to the CCSD(T) was found to be PBE0-D3, followed by PW6B95106-D3. Grimme and co-workers also recently evaluated the performance of different DFT methods (e.g., TPSS, PBE0, B3LYP, E


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that caution might be advisable when interpreting dispersioncorrected dissociation energies. In the context of dissociation energies of palladium−NHC complexes, P. Chen and co-workers used energy-resolved collision-induced experiments to deduce and compare experimental and theoretical data for the reductive elimination and ligand dissociation energies of a palladium−NHC complex.111 Overall, the authors observed a good performance of M06L, performing particularly well for dissociation energies. For instance, the experimental dissociation energy of 47.1 kcal/mol was computationally well estimated to 45.8 kcal/mol using M06L. In contrast, B3PW91 (a dispersion-free method) was observed to underestimate the same dissociation energy by approximately 9 kcal/mol. In a similar context (although also covering transition metals outside of the scope of this review), recently, P. Chen and coworkers also evaluated several DFT methods (BP86, BP86-D3, B3LYP, B3LYP-D3, B97D, PBE, PBE0, TPSS, and TPSSh) with respect to their ability to describe ligand dissociation energies of 10 different transition-metal complexes with large ligands (examples showcased in Scheme 1).112 The benchmark study

PW6B95) to compute the reaction energies of the dissociation of the Pd(II) dimer shown in Figure 8.86 The performance was

Figure 8. Investigated Pd(II) dimer with R = Ph or Cy.86

referenced against experimental reaction enthalpies and Gibbs free energy data that had previously been measured by titration calorimetry. The authors observed that the best performing method was PW6B95-D3 employing BJ damping.107,108 M06 also showed good performance, particularly when combined with Grimme’s D3-dispersion scheme, whereas DFT methods, that do not account well for dispersion, such as PBE, PBE0, and TPSS failed to describe the reaction energy. In this study, the authors also concluded that the largest source of error can be attributed to the calculation of the Gibbs free energy of solvation. The solvation energies were calculated with COSMO-RS and SMD and estimated to introduce an uncertainty of about 2−3 kcal/ mol. With respect to the accuracy of DFT-D3 and solvent models, Jacobsen and Cavallo recently evaluated DFT-D3 combined with CPCM (as the solvent model) to reproduce the ligand dissociation reaction enthalpies of several Fe- and Ru-based catalysts (although not transition metals covered in this review, but similar), such as (CO)3Fe(benzylideneacetone), (Cp)Ru− (Cl)(cyclooctadiene), (CO)3Fe(PMe3), and (CO)3Fe(PPh3). By comparing the computational results with experimental ligand dissociation reaction enthalpies, the authors observed a good performance of DFT-D3 to reproduce the experimental results of complexes, such as (CO)3Fe(benzylideneacetone) and (Cp)Ru(Cl)(cyclooctadiene). However, for phosphine ligands of different sizes, the calculations with DFT-D3 led to contradictory predictions (relative to experiments) for the exchange between small and large ligands, such as PMe3 and PPh3, and suggested that DFT-D3 may overestimate the binding energy of large ligands and organometallic complexes. This led the authors to suggest the inclusion of a cutoff distance in the dispersive term as that might be able to resolve the observed issue of DFT-D3 overestimation of bond energies between large ligands and metals. However, more recent calculations by Grimme employing DFT-D3 with COSMO-RS (instead of CPCM) as solvent model and a large basis set (def2-QZVP instead of TZVP) showed that dispersion-corrected DFT could indeed predict the experimental ligand exchange reaction between PMe3 and PPh3.109 The previously reported errors related to DFT-D3 were instead suggested to mainly be attributed to an inadequate treatment of solvation (CPCM in this case) and to a certain degree also the choice of method and basis set incompleteness (TZVP in this case). In addition, Grimme observed no general systematic errors of DFT-D3 and concluded that the introduction of a cut-off distance term for DFT-D3, as described by Jacobsen and Cavallo, would make little sense. However, in terms of qualitative accuracy, still a certain degree of binding overestimation could be observed (even when employing COSMO-RS and a large basis set),110 which indicates

Scheme 1. Performance of Selected Methods in Calculating Dissociation Energies for Reactions Involving Large Transition-Metal Complexes of Ru (a), Pt (b), and Pd (c) as Published by P. Chen and Co-workers112a

a

Calculated free energies of reaction (in kcal/mol) and deviations from the experimental values (numbers in brackets) are presented.

was performed relative to experimental gas-phase dissociation energies and showed that overall, the best performance (in terms of mean absolute deviation (MAD)) was obtained for PBE0 (MAD = 6.4 kcal/mol), whereas larger deviations were observed for BP86-D3 (MAD = 10.7 kcal/mol) and B97D (MAD = 8.6 kcal/mol). However, with respect to the palladium-based reaction (Scheme 1c), BP86-D3 was observed to perform the best, thus indicating that the performance of DFT methods may be highly system dependent. F


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3. PALLADIUM Palladium catalysis has offered the world a variety of new transformations and made numerous structural moieties more readily accessible. While in some cases the role of palladium may be apparent, frequently multiple pathways need to be considered. In even more challenging scenarios, the preferred mechanism may depend on reaction conditions, ligands, and additives.14 While experimental chemistry can give sufficient insights, often the interpretation of these results may end up being inconclusive.2,33 In such situations, turning to computational chemistry may allow to gain greater understanding of a specific chemical problem.113−122 More recently, many studies have emerged where computational chemistry has given new insight even before any experiments have been conducted.2 In recent years numerous reviews have been published that cover the contributions of computational chemistry to palladium catalysis. These include the overview of combined experimental and computational studies on various oxidation states of Pd,33 mechanisms of cross-coupling reactions,123,30,31 and C−H activation reactions.35,124,125 In the following section we aim to provide an extensive overview of computational studies on homogeneous Pd catalysis and related reactivities. Additionally, when applicable, the effects of the employed computational models will be discussed.

Scheme 2. Size of the Ligand Determines the Ligation State of the Active Pd Species during Oxidative Addition (and in catalysis in general)127,128

3.1. Coupling Reactions

3.1.1. Oxidative Addition. Oxidative addition, which is the first step in numerous catalytic cycles, is often also shown to be the rate-determining step of the reaction.31 Therefore, accurate description of this step is a prerequisite for reliable calculations of many transition-metal-catalyzed processes.126 In this context, Harvey and Fey calculated the oxidative addition of aryl halides (Cl, Br, I) to different PdLn species and correlated their computational results with kinetic data. Their findings suggest that in the reaction between PdL2 (L = PtBu3 or SPhos) and PhBr, associative displacement and not the oxidative addition is rate limiting.127,128 The use of IEF-PCM129(toluene) B3LYPD2/6-311+G(d) (aug-cc-pVTZ)//B3LYP/6-31G(d) (SDD) methodology led to a good agreement with these proposals. Using solely the B3LYP method, which poorly accounts for dispersion, failed to reproduce experimental observations by suggesting that initial dissociation of the ligand should take place. This was also concluded in a computational study from 2008 by Li et al. due to the poor description of dispersion interactions in the used B3PW91 and PBEPBE methods.130 Depending on the properties of the ligand, different pathways have been suggested to be in play: bulky and electron-rich ligands allow access to low-coordinate and highly active species via associative displacement or dissociative pathways (Scheme 2). Smaller ligands, however, were suggested to prefer bisligated pathways. This in turn makes the dissociation of one of the ligands energetically more relevant when also subsequent steps of the catalytic cycle are considered.127,131,132 The oxidative addition of CH3Br to Pd with various ligands (i.e., PPh3, PMe3, PH3, PF3) and the effect of solvation on that was computationally assessed by Yates, Maseras, and co-workers in 2011.133 Two mechanistic possibilitiesconcerted and SN2 oxidative additionwere compared based on calculations at the B3LYP-D//PCM (THF or DMF) B3LYP/6-31+G(d,p) (SDD) level of theory. The calculations suggest that for monophosphine complexes a change in the mechanism from concerted to SN2 occurs when moving from THF to polar DMF. In the case of bisphosphine complexes, the bulkier PPh3 and PMe3 complexes

favor the SN2 mechanism already in the gas phase. For both mechanisms the more electron-poor ligands stabilized the transition states the least, with the SN2 mechanism being affected much more strongly by the electronic nature of the ligand.134 In the context of Pd-catalyzed allylic alkylation, a computational study of the oxidative addition of 3-chlorocyclopentene to Pd(0)Ln complexes was undertaken by Wolf and Thiel in 2014.135 Their calculations at the CPCM (benzene) B2PLYPD3//def2-TZVPP//TPSS-D3/def2-TZVP level of theory investigated the inversion or retention (via anti or syn transition states, correspondingly) of the stereocenter in the chloride substrate, depending on the nature of the ligands and the ligation state of the complex. In the gas phase the syn pathway was suggested to be preferred in any case but only by a narrow margin in case of electron-rich ligands. In a low-dielectric medium these electron-rich ligands however were shown to switch their preference to the anti pathway. The preference for the syn pathway was explained via distortion/interaction and energy decomposition (EDA) analysis, which showed that the electrostatic component of the interaction energy (which is also highly dependent on the electronic properties of the ligand) contributes the most to the observed syn selectivity. The selectivity of oxidative addition (i.e., when multiple acceptor sites are available) can be affected by many factors, such as ligand, solvent, and additives.33 G. Fu and co-workers reported in 2000, that for the Suzuki coupling of 4-chlorophenyl triflate, PCy3 gave coupling at the C−OTf bond and PtBu3 exclusively at the C−Cl bond (Scheme 3).136 Further computational studies by Schoenebeck and Houk at the B3LYP/6-31+G(d) (LANL2DZ) level of theory revealed that the triflate is activated by a bisligated palladium complex, in line with general HOMO/LUMO reactivity considerations, with the C−OTf being the most electrophilic site.137 The C−Cl bond is activated by monoligated Pd due to the lower distortion energy associated with this transition state. In 2011, our group discovered that when using PtBu3 as a ligand, a change of the solvent, from THF to the more polar acetonitrile or DMF, also gives rise to a change in G


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(examples of located transition states are shown in Figure 9).138,139 While for a given ligation state (mono- or bisligated Pd) the selectivity was qualitatively predicted in all cases, even for smaller model ligands, the accurate quantitative prediction of whether the mono- or bisligated pathways are being favored was found to significantly depend on the chosen computational method. We have shown that the inclusion of dispersion corrections (i.e., using ωB97X-D or D3-corrected DFT methods) for the optimization steps allows for the calculation of transition states, such as the oxidative addition of Pd(PtBu3)2 to aryl triflates (Figure 10), that are inaccessible using classical DFT methods (i.e., B3LYP).87 Various methods, basis sets, and solvation models were also evaluated for their ability to predict the correct reaction pathway. Inclusion of dispersion lowered the predicted ΔΔG‡(TSbisOTf − TSmonoCl) from about 30 to 3−7 kcal/mol (calculated at the CPCM (THF) DFT/6-311+G(d)//ωB97XD/6-31G(d) (LANL2DZ) level of theory, with DFT = B3LYPD3, PBE0-D3, and M06L). COSMO-RS141 was subsequently shown to predict similar ΔΔG‡ values for the dispersioncorrected methods. Increasing the basis set size (def2-TZVP and def2-QZVP) led to an additional increase in the ΔΔG‡ values to a range of 11−15 kcal/mol (perhaps as a result of decreased BSSE142−144 effects), which was better in line with our experiments. Furthermore, the inclusion of dispersion corrections suggested that a new ligand, P(iPr)tBu2 could facilitate a switch in selectivity by allowing access to both monoligated (C−Cl activation) as well as bisligated (C−OTf activation) pathways. The predicted site selectivity ΔΔG‡ was essentially zero between the pathways, suggesting that variations in ligand concentrations should allow for switchability in selectivity. This was validated experimentally, showing exclusive selectivity for C−Cl at low concentrations and for C−OTf at high concentrations.145 An alternative oxidative addition pathway was unraveled in our studies from 2013 on the reactivity of Pd(I) dimer of the type [(tBu3P)PdBr]2. We discovered its ability to participate in halogen exchange reactions with Pd(I) bromo dimer converting various aryl iodides to the corresponding aryl bromides (Scheme 4).146 This observation prompted a mechanistic study to determine whether this is a result of a direct reaction between the Br dimer and aryl iodide that leads to the exchange or

Scheme 3. Ligand (PtBu3 and PCy3) or Solvent-Based (PtBu3 in nonpolar or polar) Switch in the Selectivity of Functionalization of C−Cl and C−OTf Bonds137,138

chemoselectivity toward triflate addition.138 Our combined computational and experimental study suggested that this selectivity switch was consistent with anionic palladium being the active species under these conditions, i.e., [LPdY]− (Y = F−, ArB(OH)3− that are potentially present under the Suzuki− Miyaura cross-coupling conditions). These computational results were then supported experimentally by switching the selectivity of the Stille reaction by the use of either KPF6 (C−Cl activation) or KF (C−OTf activation) as an additive in polar solvent (DMF). In a similar context, in 2013 Schoenebeck and co-workers recently conducted a fundamental study to evaluate if it was possible to computationally locate transition states in solvent for the oxidative addition of Pd (e.g., Pd(PtBu3), Pd(PtBu3)(MeCN), and Pd(PtBu3)F−) to C−Cl and C−OTf bonds.139 Previous computational reports had suggested that concerted oxidative addition transition states would not exist in solution.140 However, by employing both implicit (CPCM and SMD for MeCN and toluene) and explicit (by adding MeCN molecules into the model) solvation models, it was demonstrated that it was computationally possible to locate the concerted oxidative addition transition states for aryl chlorides and triflates in solvent

Figure 9. Transition state geometries for concerted oxidative addition of Pd(PtBu3) to (a) C−OTf and (b) C−Cl located by employing explicit solvation in MeCN. H


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Figure 10. Bisphosphine C−OTf (a) and C−OTs (b) oxidative addition transition states located using dispersion-corrected optimizations.87,145

L2Pd-bis(allyl) complexes. Their results, obtained at the PCM (MeCN, DMF) B3LYP/6-31G(d) level of theory indicated C(sp2)−C(sp2) bond formation to be the most favored one. Although these studies utilized more classical methods that did not account well for dispersion, the results were in line with experiments.152 The absolute barriers may likely change if dispersion is considered, but this frequently does not change the qualitative reactivity picture. Reductive elimination from higher oxidation state (+III and +IV) Pd species has also been the focus of numerous studies.153−158 The reductive elimination of C−Cl and C−O from dinuclear Pd(III) complexes was first reported by Ritter and Goddard in 2009.153−155 Later in 2011, Yates and co-workers performed a computational investigation on C−Cl and C−C bond formation from Pd(III) dimers. Considering both direct and dissociative pathways, the calculations at the CPCM (MeCN,CH2Cl2) M06/6-311+G(2d,p) (def2-QZVP)//M06/6-31G(d) (LANL2TZ) level of theory showed that in MeCN the dissociative pathway was favored whereas in less polar solvents, such as DCM, the direct pathway was preferred. Moreover, both M06 and B97D were compared in geometry optimizations as well as in energy calculations, and M06 was found to perform best in reproducing experimental data.157 The mechanism of C−O reductive elimination from Pd complexes of various oxidation states was assessed by Sanford and co-workers in 2011.159 On the basis of their calculations at the SMD (MeCN,CH2Cl2) M06 level of theory employing the unusual CEP-31G(d) basis set, different transition state geometries including 3- and 5-membered transition states were considered, and the 5-membered transition state was found to be preferred. Furthermore, chemoselectivity between C−Cl and C−OAc reductive elimination from dinuclear Pd(III) Cl/OAc complex was investigated in 2013 by Schoenebeck and co-workers employing PBE0-D3, B3PW91-D3, and M06L along with the solvation models COSMO-RS and CPCM.160 The combined experimental and computational studies suggested that the reductive elimination of Ar−Cl does not likely take place directly from the mixed Pd(III)Cl/OAc dimer. Instead, a scrambling process to give Pd(III) OAc and Pd(III) Cl dimer takes place prior to reductive elimination of Ar−Cl. Notably, in this context, additional experiments allowed to overcome conflicting computational data.

Scheme 4. Direct Reactivity of Pd(I) Dimers with Aryl Halides in the Halogen Exchange Reaction146,147

whether the dimer serves as a source for a very reactive monoligated Pd(PtBu3) species. The combined experimental and computational studies were in support of direct reactivity of the Pd(I) dimer. The experimentally measured activation free energy was shown to be within reasonable agreement with computational results.147 Whereas methods that account well for dispersion (M06L and ωB97X-D with def2-TZVP basis set and optimizations at B3LYP or ωB97X-D/6-31G(d) level of theory) were capable of accurately predicting the measured barrier, some methods employing Grimme’s D3 dispersion-correction significantly underestimated it (by up to 20 kcal/mol). Methods that do not account well for dispersion, however, predicted much greater activation free energy barriers (by up to 22 kcal/mol). 3.1.2. Reductive Elimination. Previous studies have established the trends in the reductive elimination step depending on the hybridization state of the carbon atoms involved and also how the bite angles of bidentate ligands affect the process.123,148−150 The effects of ligands in the reductive elimination from Pd complexes has been the focus of studies by Maseras and Espinet in 2009.151 Their combined computational (at the PCM (MeCN) B3LYP/6-31G(d)(SDD) level of theory) and experimental studies showed that reductive elimination from tricoordinate palladium complexes can be further facilitated with the use of electron-poor olefin additives. The employed computational methods suggest that it can lower the barrier by up to 7.3 kcal/mol, thus facilitating the difficult Pd-catalyzed alkyl−alkyl coupling. In a related study from 2010, the same authors analyzed various modes of reductive elimination from cisI


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3.1.3. Suzuki−Miyaura Coupling. The important and versatile Suzuki−Miyaura cross-coupling reaction161 was recently investigated by numerous computational studies.162−173 In 2011, Kozuch and Martin compared how different ligands (PMe3, PPh3, and PtBu3) affect the catalytic cycle and the turnover frequency of the Suzuki−Miyaura coupling.131 Various DFT methods were compared against CCSD(T) reference values to find the PCM (THF) PBE0-D3/def2-TZVPP//B97D/ def2-SV(P) methodology to be the most accurate in this specific case. The known inefficiency of PMe3 was computationally reproduced by showing that it would irreversibly lead to the formation of trans-PdL2PhBr, a dead end for the catalytic cycle (Scheme 5a). For PPh3, however, the high stability of PdL3

Scheme 6. Boronate (a) and Hydroxo (b) Mechanisms of the Suzuki−Miyaura Coupling174

Scheme 5. (a) Bisligated Mechanism in the Suzuki−Miyaura Coupling with L = PPh3 or PMe3 and the Corresponding Turnover-Limiting Intermediates; (b) Turnover-Limiting Associative Displacement Step for L = PtBu3 (d,p) (SDD) level of theory and concluded that the boronate mechanism is favored by 7.4 kcal/mol over the hydroxo mechanism. Additionally, the authors noted that optimization of the species by including the SMD solvation model systematically changed the energies by 1−3 kcal/mol and thus led to no changes in the overall energetic trends. In 2013, Buchwald and co-workers introduced an effective SPhos−Pd-based catalytic system for the Suzuki coupling of unprotected and nitrogen-rich heterocycles.179 To understand the poor reactivity of some of the used heterocycles a computational study at the PCM (THF) B3LYP/6-31+G(d,p)(LANL2DZ) level of theory was undertaken. They concluded that the inhibitory effect of some of the used heterocycles stems from the formation of inactive species such as azole-bridged dimers and not from the energetics of oxidative addition and reductive steps. The SPhos ligand was also computationally assessed at the IEF-PCM (THF) PBE0-D3/def2-TZVPP// B97D/def2-SV(P) level of theory in the context of Suzuki coupling by Kozuch and Martin in 2011.180 It was shown that the high stability of Pd(SPhos)2 species greatly affects the turnover frequency (TOF) of the catalytic cycle. On the basis of this observation, a new ligand, InPhos, was proposed and theoretically shown to provide much higher TOF values than its counterpart due to increased steric bulk that destabilizes the PdL2 species. Sköld, Norrby and co-workers performed calculations at the PBF(dioxane, DMF) B3LYP-D3/6-31G(d,p)//B3LYP/6-31G(d,p) (LACVP**) level of theory and were able to explain the beneficial effect of 1,4-benzoquinone in a domino Heck/Suzuki coupling of chelating olefins with two equivalents of arylboronic acid. Their results indicate that benzoquinone prevents the occurrence of β-hydride elimination after the initial migratory insertion of olefin into the Pd−Ar bond, and instead, another aryl group is transmetalated to the Pd center.181 In the same study, a comparison between M06 and B3LYP-D3 methods showed the former to lower the relative energies of the species involved while still predicting the same reactivity trend. As the catalytically active Pd(0) complexes are often prone to oxidation by air, there is great need for ways to create more stable catalysts. One way to overcome this issue is through the use of precatalysts.182 In this context, Hazari and Balcells studied a class of (μ-allyl)(μ-Cl)Pd2(NHC)2 dimers as the source for highly active monoligated Pd(0).183 Calculations performed at the SMD (iPrOH) M06L/6-311+G(d,p) (SDD(d,f))//SMD

species was found to be the turnover-limiting factor (Scheme 5a). Finally, also for PtBu3 the ligand displacement step is shown to be rate determining (Scheme 5b). However, as a monoligated mechanism is in play, the energetic cost of the oxidative addition process is diminished, thus leading to a much higher turnover frequency (TOF). These results are also in line with previous studies on the oxidative addition of aryl halides to Pd with various ligands.127,128 In 2014, Maseras et al. investigated the transmetalation step of the Suzuki−Miyaura coupling in the presence of water to determine which of the two mechanisms is operative: the boronate mechanism where R−B(OH)3− transfers the R group or the hydroxo pathway through an [LnPd(R′)(OH)] intermediate (Scheme 6).174 Previous computational and experimental studies have often suggested the boronate mechanism to be preferred;169,175,176 however, further experimental data has also appeared supporting the hydroxo mechanism.177,178 In this context, Maseras and co-workers also assessed all possible pathways and included additional water molecules coordinated to the boronate, leading to an explicit/implicit solvation model. Calculations were performed at SMD (THF)//M06/6-31GJ


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(iPrOH) M06L/6-31G(d) (SDD) level of theory in combination with experimental studies uncovered a mechanism for the activation of these Pd(I) dimers by various nucleophiles (i.e., Nu = isopropanol or olefins) to release Nu−Pd(0)−NHC and Pd(II). Various studies have also covered stereo- or site-selectivity in Suzuki−Miyaura coupling reactions.184 For instance, calculations by Maseras et al. in 2009 at the PCM (ε = 11.7 for tert-amyl alcohol) B3LYP/6-31+G(d,p) (SDD) level of theory explained that the fast and stereoselective Suzuki coupling of α-bromo sulfoxides185 is the result of a SN2-type oxidative addition that results in an inversion of the stereocenter.186 Additionally, the sulfinyl substituent was shown to lower the barrier of oxidative addition through coordination to the Pd center in the corresponding transition state. In 2010, selectivity between activating C(sp2)−Br and C(sp3)−Br bonds was also compared both experimentally and computationally by Maseras and coworkers.187 The chosen computational method consisted of QM methodology (PCM (THF) B3LYP/6-31+G(d,p) (SDD)) for monophosphine systems and ONIOM QM/MM methodology (PCM (THF) B3LYP/6-31+G(d,p) (SDD):UFF) for bisphosphine systems. The authors suggested that less hindered or bidentate phosphine ligands (i.e., PPh3 and Xantphos) promote the addition to the C(sp3)−Br bond because the SN2 oxidative addition TS is sterically less encumbered than the concerted oxidative addition TS of C(sp2)−Br bonds (Scheme 7). Consequently, the latter oxidative addition prefers bulkier monophosphine ligands (i.e., PCy3 and P(o-tolyl)3).

Scheme 8. Cyclic and Open Mechanisms of the Stille Coupling198

organostannane reagent and, therefore, inhibits the reaction.203 On the other hand, smaller ligands, such as PMe3 and PPhMe2, would also inhibit the rate of transmetalation as they facilitate the formation of a stable trans-L2Pd(Ph)(X) intermediate which raises the activation barrier for transmetalation. This can, however, be avoided by using slightly bulkier PPh3 and PPh2Me ligands. Similar observations in the context of Suzuki−Miyaura coupling are also discussed above.131 The use of gold as a cocatalyst has been shown to promote Stille coupling with otherwise unreactive Ar−SnBu3 reagents (i.e., where Ar is sterically crowded).204 Calculations at the SMD (MeCN) ωB97X-D/6-31G(d,p) (LANL2DZ) level of theory by Espinet and co-workers in 2014 indicated that this effect could stem from the lower activation barriers of the Sn/Au and subsequent Au/Pd transmetalation steps when compared to the direct Sn/Pd transmetalation. Au/Pd transmetalation was also studied by Espinet and co-workers in 2012 using the ωB97X-D/ 6-31G(d) (LANL2DZ) methodology.205 They concluded that transmetallating an aryl group from Au to Pd is thermodynamically not feasible and would require irreversible reductive elimination as a driving force. The release of a ligand is required for the formation of a bimetallic Au−Pd system, and therefore, only more weakly coordinating arsane ligands are able to promote this reaction.204 Kinetic studies indicate aryl for Cl exchange to be the rate-limiting step, and calculations successfully confirmed this observation. Results, obtained by using the B3LYP method, however, showed the reversal of the relative barriers and thus failed to correctly describe the reactivity. 3.1.5. Hiyama Coupling. Few computational studies have set their focus on the Pd-catalyzed C−X/C−Si Hiyama coupling. Among them Hiyama et al. investigated the role of fluoride additives in Pd-catalyzed coupling of vinyl iodide and vinylsilane in 2008.206 Their computational study at the B3LYP/6311G(d)//B3LYP/6-31G(d)(LANL2DZ) level of theory (validated against MP4(SDQ)207,208 level calculations) concluded that the substitution of the iodo ligand on palladium and the attack of the fluoride anion on the silane reagent act both as viable pathways through which fluoride anions could aid the reaction. A computational study by Qi and co-workers suggested that in addition to the acetate anion, also a weakly coordinating tetrafluoroborate anion might coordinate the silane and assist in the transmetallation step of Hiyama coupling.209

Scheme 7. Varying the Steric Bulk of the Ligand Allows for Switching Between C(sp3)-Br and C(sp2)-Br Functionalization187

3.1.4. Stille Coupling. Computational studies of the Stille reaction188 have given many new insights into potential intermediates, possible reaction pathways, and the effects of different ligands.189−193 In particular, the mechanism of transmetalation in the Stille cross-coupling reaction has been the focus of a variety of studies.194,195 In 2008, Á lvarez and coworkers performed a computational study at the B3LYP/631G(d) (SDD) level of theory to confirm the proposal made by Casado and Espinet196,197 that an open mechanism for the transmetalation step is operative in the case of cationic Pd(II) complexes (i.e., after the oxidative addition of vinyl triflates).198 Anionic ligands which are less prone to dissociation (i.e., halides), however, facilitate a cyclic mechanism (Scheme 8). In 2009, experimental results by G. Fu,199−201 as well as by Farina and Krishna202 prompted Yates and Ariafard to perform a computational study on the role of ligands in the transmetallation step at the B3LYP/6-311+G(2d,p)(LANL2TZ+(3d for Cs and Sn; 3f for Pd))//CPCM (dioxane)//B3LYP/6-31G(d)(LANL2DZ) level of theory. Their results indicated that the use of large ligands (i.e., PtBu3) hinders the coordination of the K


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3.1.6. Negishi Coupling. The Pd-catalyzed coupling of aryl halides with organozinc reagents has been in the focus of some computational studies over these past few years.210 A study of the transmetalation step in the Negishi reaction was undertaken in 2011 by Ujaque, Espinet, and co-workers at the SMD (THF) M06/TZVP (DGDZVP)//M06/6-31G(d)(LANL2DZ) level of theory.211 They noted that the presence of additional ligand profoundly affects the reaction mechanism. In the absence of the ligand (PPh2Me), a highly reactive cationic complex trans[L2Pd(Me)(THF)]+ is formed which readily reacts with the ZnMe2 nucleophile (Scheme 9). An additional ligand, however, Scheme 9. Ligand-Induced Trapping of the Active Catalysta

Figure 11. Regioselectivity of Mizoroki−Heck coupling depending on the number of tBu groups on the ligand.222

a

Furthermore, the prediction of selectivity additionally benefited from the inclusion of an additional DFT-D correction term. On the basis of calculations performed at the PBF (THF) B3LYP/LACVP** level of theory, in 2008 Norrby, Andersson, and co-workers also established that in the asymmetric Heck coupling of aryl triflates with dihydrofurans, Halpern-type selectivity223 governs the outcome of the reaction.224 This means that the major isomer is formed from one of the higher energy pre-insertion intermediates (Scheme 10). While the trans

ZnMe2 facilitates the formation of cis complex.211

leads to the formation of a stable [L3Pd(Me)]+ which is not capable of participating in the transmetalation reaction. ZnMe2 was also shown to facilitate the cis−trans isomerization during the transmetalation. The latter was also observed in a related study from 2010 for ZnMeCl as a coupling partner.212 The isomerization was shown to take place by reverse transmetalation of the trans-[L2PdMe2] complex back to trans-[L2Pd(Me)Cl] and then transmetallating that to cis-[L2 PdMe 2 ]. As a consequence of this fast transmetalation equilibrium (Scheme 9), eventually homocoupling products may form. The additional transmetalation steps that lead to homocoupling products were also investigated in 2009 by Lei et al. for Pd-catalyzed Ar−Ar Negishi coupling.213 The interactions between Pd and Zn have been found to be beneficial for reductive elimination in the Negishi coupling.214,215 As ZnX2 has been suggested not to dissociate from the Pd complex after the transmetalation reaction, the steric crowding on palladium is increased and the reductive elimination can occur more readily. In the case of 1,3-bis(2,6diisopropylphenyl)imidazole-2-ylidene (IPr) as a ligand on Pd, calculations by Chass and co-workers at the PCM (THF) B3LYP/DZVP level of theory in conjunction with bond critical point (BCP) analysis216 indicated that weak interactions exist between the hydrogen atoms of the iPr groups of the ligand and the Pd center.215 3.1.7. Heck Coupling. A number of computational studies into various aspects of the Pd-catalyzed Heck reaction have been performed over recent years.217−221 The dependence of regioselectivity on the number of tBu groups on the ligand was calculated (using PBF (DMF) M06-D/ LACVP*//B3LYP/LACVP* methodology) for a Pd-catalyzed Mizoroki−Heck coupling between aryl halide and ethyl vinyl ether by Norrby and co-workers in 2012 (Figure 11).222 Similar to the above example,138 consideration of an anionic mechanism, by replacing one of the PtBu3 ligands with a second halide ligand, led to a better agreement with the observed selectivity.

Scheme 10. Halpern-Type Selectivitya

a Less favored trans-Ph−P complex leads to the formation of the major coupling product.224

Ph−N arrangement is more favorable over the trans Ph−P arrangement, the higher barrier of the subsequent furan insertion and the lower stability of the formed carbopalladated species make the trans Ph−N pathway less productive. Another stereoselective variant of the Heck coupling (Figure 12) between acyclic alkenols and aryl diazonium salts yielding a saturated carbonyl product instead of a more general unsaturated

Figure 12. Pd-catalyzed redox-relay Heck cross-coupling yielding a carbonyl product via series of β-hydride eliminations.226−228 L


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of the alkyne is suggested to take place in the Pd-alkyne πcomplex. Similar observations regarding the preferred mode of activating the alkyne were made by Burk and co-workers after having assessed various alkyne deprotonation pathways.233 The authors concluded that the alkyne is deprotonated by the nbutylamine base after its coordination to the (PPh3)Pd(Ph)Br complex.

alcohol Heck product225 was studied by Wiest, Norrby, Sigman, and co-workers226,227 and also independently by Wang and coworkers (using similar SMD (DMF) M06/6-311++G(d,p)// B3LYP/6-31G(d) (LANL2DZ or SDD) levels of theory).228 They determined that a series of β-hydride eliminations and readditions after the migratory insertion of the olefin move the Pd atom closer to the electronegative oxygen, eventually leading to the formation of the carbonyl product. Enantioselectivity of the reaction is controlled by the steric repulsion of the ligand’s tBu group. Various methods were also compared by Wiest and co-workers to find that B3LYP and also six other methods that better account for dispersion were able to predict similar energetic trends for the entire reaction pathway.226 In 2013, Ujaque et al. studied the competing Heck-syndesilylation, Heck-transmetalation, and Hiyama coupling routes, depicted in Scheme 11, for a hydroxide-promoted reaction

3.2. Aryl Trifluoromethylation

The reductive elimination of ArCF3 from palladium is one of the key challenges in developing Pd(0)/Pd(II)-catalyzed trifluoromethylation reactions.234−236 Xantphos was the first ligand shown to be able to enable this.237 A computational study from 2011 by Anstaett and Schoenebeck using the ONIOM B3LYP/631+G(d,p) (LANL2DZ):HF/LANL2MB methodology explained that the origin of this superior reactivity stems from the greater destabilization of the reactant complex relative to the transition state, which overall lowers the barrier of reductive elimination from 33.9 kcal/mol in the case of dppe to 25.7 kcal/ mol for Xantphos (Figure 13).238 In 2012, similar results were

Scheme 11. Competing Heck-syn-Desilylation, Heck Transmetallation, and Hiyama Coupling Routes in Hydroxide-Promoted Pd-Catalyzed Coupling of Aryl Iodides with Vinyl Silanes229

between aryl iodides and vinyl silanes by combining experimental and computational (at SMD (H2O) M06/6-311++G(d,p)// M06/6-31G(d,p) (SDD+f) level of theory) approaches.229 Under aqueous conditions where the nucleophilicity of hydroxide anions is lowered, the Hiyama coupling was clearly disfavored. Instead of initial C−Si activation and transmetalation, the vinyl silane inserts into the Pd−Ar bond. The observed styrene product is shown to form via a Heck-syn-desilylation route with the β-silyl-styrene reinserting to the Pd−H bond and forming an O-bound palladacycle. A syn Pd−Si β-elimination step subsequently forms the styrene product. 3.1.8. Sonogashira Cross-Coupling. The development of a copper-free Sonogashira reaction has received attention in recent years as a more versatile alternative for the classical reaction conditions.230,231 Computational studies in this context have focused on the mechanistic details of this transformation and especially on the various potential modes for alkyne activation. On the basis of calculations performed at the B3LYP/6-31G(d,p)/6-31+G(d) (SDD+d,f) level of theory, Ujaque et al. concluded that cationic ([cis-(PH3)2PdPh(η2-Halkyne)]+ mediated), anionic ([(PH3)Pd(alkyne)(Ph)I]− mediated), and ionic ([trans-(PH3)2PdPh(base)]+ I− mediated) mechanisms all can be operative in the Pd(PH3)2-catalyzed coupling of aryl iodides with alkynes using pyrrolidine as a base.232 Only the carbopalladation mechanism was found to have prohibitively high barriers. Their calculations also showed that the preferred pathway may depend on the electronic nature of the substituents on the alkyne phenyl group. The deprotonation

Figure 13. Effective Xantphos ligand for the reductive elimination of Ar−CF3 from Pd(II).238 Computational design and experimental verification of a ligand where electrostatic repulsion facilitates the reductive elimination.241

also obtained by Macgregor, Grushin, and co-workers when studying the Xantphos system. A good agreement between the experimentally measured barrier of ΔH‡ = 25.9 kcal/mol and a predicted barrier of ΔH‡calc = 24.8 kcal/mol and ΔG‡calc = 25.0 kcal/mol (at the B97D/6-31G(d,p) (SDD) level of theory) was reached.239 Various other tested methods predicted smaller barriers, especially those not accounting well for dispersion effects. Furthermore, various methods were tested on a reaction between (Xantphos)Pd(Ph)CF3 and excess Xantphos that establishes an equilibrium with trans-[(η1-Xantphos)2Pd(Ph)CF3] in a 1:50 ratio (suggesting a ΔGrxn of ∼2 kcal/mol). However, several GGA and hybrid-GGA methods predicted this equilibrium to have a ΔGrxn of 16−20 kcal/mol and dispersioncorrected methods ΔGrxn of from −14 to −17 kcal/mol. Meanwhile, Buchwald et al. published a protocol for Pd(0)catalyzed trifluoromethylation of aryl chlorides using BrettPhos or RuPhos as ligands for which a barrier of 22 kcal/mol was predicted for the reductive elimination at the B3LYP/6-311+ M


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+G(2d,p)//B3LYP/6-31G(d) (LANL2DZ) level of theory.240 In 2014, Schoenebeck and co-workers showed that by increasing the electrostatic repulsion from the ligand toward the aryl and CF3 groups on Pd, while decreasing the size of substituents that would otherwise destabilize the transition state, the first small bite-angled ligand to trigger the reductive elimination was computationally designed and experimentally verified (Figure 13).241 Additionally, kinetic measurements (ΔH‡ = 27.9 ± 1.6 kcal/mol) were in good agreement with computational predictions. Reductive elimination of Ar−CF3 from Pd can also be promoted by increasing its oxidation state to +IV as shown by Sanford and co-workers.158,242 Their computational mechanistic study at the SMD (nitrobenzene) M06/CEP-31G(d) level of theory predicted that changing the ligand from bipyridine (bpy) to N,N,N′,N′-tetramethylethane-1,2-diamine (tmeda) should lower the barrier toward reductive elimination of Ar−CF3 from 80 °C (for L = bpy) to room temperature (for L = tmeda), which was subsequently verified experimentally. Furthermore, the authors showed that the barrier of reductive elimination is decreased by increasing the electron-donating nature of the substituent on the aryl group, which was in line with the observed experimental conversions. Lastly, the involvement of Pd(IV) intermediate was also proposed by J.-Q. Yu and co-workers to be involved in a Pd(II) catalyzed electrophilic trifluoromethylation reaction.243

active species, but the resting states of the catalytic cycle are bimetallic. The reaction proceeds via a Pd(II)/Pd(IV) catalytic cycle which consists of initial C−H activation of the amino acid and subsequent oxidative addition of aryl iodide to the Pd(II) complex. This mechanism was shown to be favored over the alternative mechanism where the aryl group would be transmetalated from another L2Pd(Ar)X complex to the Pd−Alkyl complex. The Pd(II)/Pd(IV) catalytic cycle was shown to be operative also in another case of C(sp3)−H activation reaction of amino acid derivatives.260 In this study from 2015, the authors, based on the calculations performed at the SMD (DCE) M06L/ 6-311++G(d,p)//BP86/6-31G(d)(SDD) level of theory, also described a previously unreported H-bonding interaction in the key C−H activation transition state that involves two bicarbonate anions (Scheme 12). Scheme 12. Pd-Catalyzed C(sp3)−H Activation That Proceeds via an Anionic Bis(bicarbonate) C−H Activation Transition State and a Pd(IV) Intermediate260

3.3. C−H Bond Activation

The direct modification of C−H bonds is considered the most atom-economical way of functionalizing compounds. Therefore, there is great motivation to further develop such catalytic systems. This has already resulted in numerous mechanistic studies.35,244−253 Mechanistically, a variety of different possibilities have been considered for TM-catalyzed C−H activation reactions, among them are (a) oxidative addition, (b) σ-bond metathesis, (c) electrophilic substitution, (d) 1,2-addition, and (e) ambiphilic metal ligand activation (AMLA) via 4- (σ-complex-assisted metathesis, σ-CAM) and 6-membered (concerted metalation deprotonation, CMD) transition states.35,125 For palladium, four modes of catalysis are most commonly considered: Pd(II)/ Pd(0), Pd(II)/Pd(IV), Pd(0)/Pd(II)/Pd(IV), and Pd(0)/Pd(II).254 Such mechanistic diversity often requires multiple scenarios to be considered when performing a study on a specific case of C−H activation reaction. The introduction of the CMD mechanism in 2006 has profoundly reshaped the current understanding of many of C−H activation reactions. Many computational studies have recently shown the latter to better explain experimental observations.255−257 In that context, in 2008 Fagnou and co-workers analyzed the characteristics of the CMD mechanism using distortion/interaction analysis. Their calculations indicated that while the distortion energy term for the palladium complex has a rather narrow span, it varies significantly for aromatic substrates.258 The interaction energy term, however, greatly stabilizes the transition state, thus leading to the observed relatively high reactivity. The Pd-catalyzed C(sp3)−H activation that leads to γarylation of N-protected amino acids was studied by Alonso and co-workers in 2014 by combining experiments and computations at the CPCM (MeCN) M06/6-311+G(2df,2p)//B3LYP/6-31G(d)(SDD) level of theory.259 They concluded that monomeric Pd(II) complexes are the catalytically

The site selectivities of C−H activation reactions have received significant attention from computational chemists in recent years.261−267 In 2011, Y. Fu and co-workers performed a computational study at the CPCM (toluene) M06/6-311+G(d,p)(SDD)//B3LYP/6-31G(d)(LANL2DZ) level of theory to show that the ligand-dependent α- or β-selectivity in the arylation of thiophenes stems from the preference for two different mechanistic pathways (Scheme 13).268 The 2,2′Scheme 13. Ligand- or Counterion-Controlled Selectivity in the C−H Activation of Thiophene268,269

bipyridyl ligand facilitates the metalation/deprotonation pathway, leading to α-arylated product. Phosphite ligands, however, favor the Heck-type arylation mechanism along with anti-βhydride elimination, which preferably leads to the β-arylated product. SEAr was considered as a third option but was disregarded because the crucial Wheland intermediates could not be located. In 2012, Grimme, Itami, and co-workers studied the counteranion-dependent selectivity in the arylation of N


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31G(d,p)(LANL2DZ) methodology, can help to predict the regioselectivity of C−H activation of heteroaromatic compounds.271 In 2014, Houk and J.-Q. Yu undertook a study to explain the observed meta selectivity in Pd- and Ag-catalyzed directed C−H activation reaction using the M06/6-311+ +G(d,p)(SDD)//B3LYP/6-31G(d)(LANL2DZ) methodology (Scheme 15a).272 Some of their results were also validated

thiophenes using the COSMO(DCE) B2PLYP-D3/def2QZVPP//TPSS-D3/def2-TZVP methodology.269 In the case of weakly basic anions, the Pd(II) intermediate exists as a cationic complex, which can react with the thiophene only via reversible carbopalladation that preferably leads to β-arylated product. More basic counteranions, however, make deprotonation the regioselectivity-determining step. Similar selectivity-switching effects of acetate and carbonate ligands were studied in 2013 by Schoenebeck and Sanford for the [BzqPd(II)X]2 and 1,3-dimethoxybenzene system (Scheme 14).270 Regardless of the nature of the base, the initial C−H

Scheme 15. Meta-Selective C−H Activation Reactions: (a) Nitrile Directing Group on a Long Tether Places the Ag and Pd Atoms in the Optimal Position;272 (b) Steric Repulsion between the Ligand and the R Group Directs Pd to the Meta Position274

Scheme 14. (a) Base-Dependent Selectivity in Oxidative C−H Activation, and (b) the Novel Dinuclear C−H Activation Transition State270

against MP2 and CCSD(T) calculations. The selectivity was reached through a Pd−Ag heterodimeric complex, which while coordinated to the nitrile directing group places an acetate anion next to the meta C−H position. Alternative mechanisms involving mono- and oligomeric Pd complexes were shown to not be operative. A similar bimetallic Pd−Ag complex was also discussed in the context of ortho C−H activation by Sunoj and Schaefer in 2014.273 The preference for meta-selective C−H activation was also studied in 2011 by Zhang et al. at the CPCM (benzene) B3LYP/6-311+G(d,p)(SDD)//B3LYP/6-31G(d)(LANL2DZ) level theory (Scheme 15b).274 They summarized that steric repulsion between a pyridine ligand and substrate directs the reaction to the meta position and in some cases, due to electronic effects, to para C−H activation. Controlling the stereoselectivity in C−H activation is also a challenging task that could be achieved using chiral monoprotected amino acids as ligands.275 In 2012, Musaev and J.-Q. Yu studied the mechanism of this reaction at the PCM (THF) B3LYP/6-31G(d,p)(LANL2DZ) level of theory and found that the reaction takes place via initial cleavage of the N−H bond. The second acetate then activates the ortho C−H bond and transfers this proton to the ligand. The origin of enantioselectivity was attributed to steric repulsions in the transition states of the proposed pathway (Figure 14). To explain why Pd-catalyzed coupling of β-keto esters and indoles leads to the formation of β′-aryl cross-dehydrogenation

activation (that could potentially proceed either via a mononuclear or a novel dinuclear transition state) was predicted to favor the ortho/para position and the reductive elimination the meta/meta position. Instead, the calculations (performed at the COSMO-RS(DMSO/dimethoxybenzene = 50/300) M06L/ 6-311++G(d,p)(SDD)//ωB97X/6-31G(d) (LANL2DZ) level of theory) suggested that the nature of the base rendered either the C−H activation (by carbonate) or the reductive elimination (by acetate) overall selectivity determining. From a chemical perspective, this was manifested in the ability of acetate or carbonate to reverse the initial C−H activation step. Thus, to determine whether this was the case, several reversibility experiments were conducted. Among them was an acid-trapping experiment where MgO was added to the acetate system to catch the released acetic acid and lower the reversibility of the reaction. Theoretically, this should promote the formation of ortho/para product, and indeed this was experimentally confirmed. In 2012, Ess and co-workers showed that the correlation between the C−H activation barrier height and the Pd−C bond energy in the transition state, calculated using the M06/6O


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calculations, performed at the SMD (toluene) M06/6-31G(d,p)//B3LYP/6-31G(d,p)(LANL2DZ) level of theory, they found that the phosphate ligands could replace the acetate anions on palladium which would substantially lower the activation barrier of the reaction. The Wacker-type mechanism was found to be preferred over the allylic C−H activation pathway and suggested to operate via an initial proton abstraction from the cyclobutanol by an outer-sphere acetate which also invokes the ring expansion. The catalytic cycle is then closed by ligand-toligand proton transfer and β-hydrogen abstraction steps. Furthermore, the authors established that optimization at the SMD (toluene) M06/6-31G(d,p)(LANL2DZ) level of theory gave analogous energetic trends as using the aforementioned methodology. Comparisons were also made with the results obtained from applying the extended free volume theory corrections by Whitesides,280 which are designed to account for the errors in the entropy term that arise from shifting from gas phase to solution.

Figure 14. Enantioselective-directed C−H activation using monoprotected amino acid as a ligand.275

product Pihko and Pàpai undertook a combined experimental and computational (at the ωB97XD/DZP(SDD) level of theory) study.276 They discovered that the reaction proceeds via two catalytic cycles. The first of them is the indole-assisted tautomerization of the ester and subsequent proton-assisted electron transfer which yields an enone intermediate and Pd(0). The second cycle is the coupling of the enone and indole which takes place via the classical concerted metalation deprotonation (CMD) mechanism. A thorough investigation of Pd-catalyzed ortho-alkoxylation of N-methoxybenzamide in methanol was undertaken by Sunoj and Anand.277 Calculations at the SMD (MeOH) B3LYP, M06, M06-2X/6-31+G(d,p)//B3LYP/6-31G(d)(LANL2DZ) level of theory, with additional validation using the CCSD(T) method, gave insights into proton transfer processes in strongly coordinating solvents. They showed that C−O bond-forming reductive elimination takes place via an outer-sphere mechanism (ΔΔG‡ = 6−9 kcal/mol compared to the direct inner-sphere reductive elimination transition state, see Figure 15). Addition-

3.5. Cyclization Reactions

Understanding the mechanisms of cyclization reactions and the factors governing their selectivities is a prerequisite for the development of new reactions leading to the formation of desired ring systems. Several computational studies have focused on problems such as the effect of Pd oxidation state,281 cyclotrimerization of norbornenes,282 selectivity between enolate arylation vs acylation/nucleophilic addition,283,284 intramolecular diamination,285 and Pd and chiral amine cocatalysis.286 Studies on the intramolecular Pauson−Khand reaction (PKR) by Wiest, Wu, and co-workers focused on a PdCl2−thiourea catalysis and its efficiency (Scheme 16).287 Their calculations at Scheme 16. Pd(II)-Catalyzed Intramolecular Pauson−Khand Reaction Proceeding via Pd(IV) Intermediate and Not the Classical PKR Mechanism287

Figure 15. Outer-sphere acetate-mediated reductive elimination of Ar− OMe.277

ally, the preceding nitrogen deprotonation and C−H activation in the initial steps of the reaction are facilitated by relay proton transfer processes via primary (acetate/acetic acid ligands) and secondary (methanol molecules) coordination spheres around the palladium. 3.4. Allylic Substitution

Sunoj and Jindal studied the cooperative asymmetric multicatalytic Tsuji−Trost allylation of aldehydes using the SMD (toluene) M06/6-31G(d,p)//B3LYP/6-31G(d,p)(LANL2DZ) methodology.278 They reported that an achiral organocatalyst first activates the aldehyde as an enamine. Enantioselectivity is then induced through hydrogen bonding between the enamine nitrogen and a chiral BINOL−phosphate which acts more as a counterion than a ligand in the stereocontrolling transition state. In the Pd-catalyzed formation of spirocyclic indene from indenyl cyclobutanol, an interesting role of ligand exchange was uncovered by Sunoj and Jindal.279 On the basis of the

the PCM (THF) BP86/6-31+G(d) (SDD) level of theory were able to rule out the involvement of the classical PKR mechanism, effective for Co-catalyzed reaction. Both Pd(0) and Pd(II) pathways gave prohibitively high barriers for the initial C−C coupling step. Additionally, this mechanism is not able to explain the observed stereochemistry (which is opposite from the classical PKR) and the essential role of the chloride anion. P


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Instead, the authors proposed a new mechanism, consisting of cis insertion of the alkyne into Pd−Cl bond, alkene insertion into the Pd−C bond, tetrahydrofuran ring formation followed by CO insertion into the Pd−C bond, vinylic C−Cl bond oxidative addition, Pd(IV) intermediate formation, and last a C(sp2)− C(O) reductive elimination. In a similar context, Pd(0)/phosphite-catalyzed [3 + 2] intramolecular cycloadditions of alkyl-5-enylidene- and alkyl-5ynylidenecyclopropanes were studied by Cárdenas and coworkers.288,289 Preferred mechanisms and factors determining the observed stereochemistry were determined for both substrates using calculations at the PCM (MeCN289) B3LYP/ 6-311+G(2df,2p)(SDD)//B3LYP/6-31G(d)(LANL2DZ) level of theory. Wang et al. hypothesized that in the cyclization of ene−yne− ketones to yield 2-alkenyl-substituted furans, a palladium carbene intermediate may be involved.290 Computational studies at the M06/6-311++G(d,p)(SDD)//B3LYP/6-31G(d)(LANL2DZ) level of theory led to results that were indeed found to support that hypothesis. Paton and Anderson presented a procedure for Pd-catalyzed azacyclization of alkynylcarbonates which can yield either alkynyl azacycles or cyclic dienamides, depending on the bite angle of the ligand used.291 Calculations performed at the ωB97X-D/def2TZVPP (for describing the electronic structure in small model systems) and 6-31G(d)(LANL2DZ) (for calculations on larger model systems) level of theory suggest that increasing the bite angle weakens the metal−allenyl bonding in the corresponding intermediates and thus lowers the LUMO energy. As a result, the terminal carbons of the allenyl fragment are more susceptible toward a nucleophilic attack, thus leading to the formation of alkynyl azacycle product.

Figure 16. Preoxidative addition π complexation, ring hopping, and oxidative addition of Ni to aryl bromides and chlorides (L = dppp).301

KIE values for C atoms away from the C−X (X = Br, Cl), suggesting that also these atoms are involved prior to oxidative addition). 4.1.2. Suzuki Coupling. A computational study from 2012 by Y. Fu and co-workers explored the mechanistic possibilities for a previously reported Ni-catalyzed Suzuki coupling of alkyl halides.302 Calculations at the PCM (dioxane) B3PW91/6311+G(2d,p)(SDD)//B3PW91/D95 V303(LANL2DZ) level of theory suggested that a Ni(I)/Ni(III) catalytic cycle is operative as opposed to the usual Ni(0)/Ni(II) cycle (Figure 17).

4. NICKEL In recent years nickel has found use in a variety of unique reactions.292,293 Similar to Pd chemistry, catalytic cycles for Ni also follow the Ni(0)/Ni(II) pathway. However, as opposed to Pd, odd oxidation states, such as in Ni(I)/Ni(III) cycles, can be more readily accessible and possibly involved in numerous Nicatalyzed transformations. The highest oxidation state of +IV, however, is quite uncommon in organonickel chemistry,294 as opposed to Pd where numerous catalytic cycles involve Pd(IV) intermediates.295−298 The aforementioned factors have increased the interest from the chemical community toward Ni catalysis in recent years.299 However, to further develop the scope and efficiency of this chemistry, it is imperative that the mechanistic processes involved are also rationalized. Thus, the following section will provide an overview of computational studies that have provided significant insights into the nature of Ni-catalyzed processes. 4.1. Coupling Reactions

Figure 17. Proposed Ni(I)/Ni(III) catalytic cycle for the Ni-catalyzed Suzuki coupling of alkyl halides.302

4.1.1. Oxidative Addition. The interaction between aromatic halides and Ni(0) was extensively studied by Allen and Locklin using the B3LYP-D3/TZ2P(LANL2TZ(f)LANL08d300) methodology and validation against CCSD(T) results.301 They pointed out that the π complexation of haloarenes with Ni(0) is irreversible and could initially take place at any C−C bond of the aromatic ring. To then reach the bond where oxidative addition could take place, a series of ringhopping steps has to occur (Figure 16). These calculated pathways were found to be in good agreement with the results from 13C NMR kinetic isotope effect (KIE) studies (with positive

Additionally, the order of elementary steps is switched with the first step being alkyl transmetalation (from a trialkyl borane reagent to the LNiX catalyst, with X = Cl, Br, I; L = 1,2-diamine or bathophenanthroline derivative). This is followed by oxidative addition of alkyl bromide via bromine abstraction and radical recombination to yield a LNi(alkyl)2Br intermediate. Tertiary halides were shown to be unreactive due to a prohibitively high barrier of reductive elimination relative to the most stable triplet Ni(II) intermediate. Q


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4.1.3. Kumada Coupling. In 2014, Hu and co-workers performed a combined experimental and computational study (using the COSMO-RS(THF) PBE0-dDsC304/TZ2P//M06/ def2-SVP methodology) on the Ni-catalyzed aryl−alkyl Kumada coupling reaction.305 The authors concluded that the aryl−alkyl coupling involved a Ni(I)/Ni(III) catalytic cycle, in which the transmetalation was deduced to be the turnover-determining step. The authors also suggested that the transmetalation may involve a bimetallic pathway, in which two Ni(II) complexes are required to supply two electrons to the alkyl halide. In 2009, Nakamura et al. reported306 an accelerating effect of hydroxyphosphine ligands in the Ni-catalyzed coupling of unreactive aryl electrophiles (fluorides, chlorides, carbamates, and phosphates) and Grignard reagents. Calculations, performed at the B3LYP/6-31G(d) level of theory, suggested that this effect is a result of coordination of ArMgX to the pendant hydroxyl group that allows for a cooperative push−pull action that is depicted in Figure 18, which in turn lowers the barrier of C−X

asymmetric steric hindrance of the S-Pybox ligand significantly affects the relative barriers for the elimination of S and R enantiomers (Figure 19).

Figure 19. Enantioselective Ni-catalyzed Negishi coupling of racemic secondary electrophiles.310

4.1.5. Heck Coupling. The importance of cationic nickel intermediates in Ni(0)/Ni(II)-catalyzed Heck coupling of aryl triflates was deduced in a 2012 study (at the PBF (THF) B3LYPD3//B3LYP/6-31G(d)(LACVP*) level of theory) by Norrby and Skrydstrup.311 The facile dissociation of the triflate anion is suggested to result in formation of a cationic Ni(II) complex, which due to its electron-deficient nature can easily bind other ligands such as olefins. β-Hydride elimination was determined to be the rate-limiting step of the reaction. However, this step is rendered inaccessible when coordinating functional groups (i.e., carbonyls) are present in the reaction mixture as they block the free coordination site on Ni. 4.1.6. Alkyne−Aldehyde Coupling. Houk and co-workers (at the B3LYP/6-31G(d) (LANL2DZ) level of theory) investigated the Ni-catalyzed alkyne−aldehyde coupling reaction in 2009.312 By qualitatively comparing the different mechanistic possibilities, the authors suggested that the favored mechanism for the alkyne−aldehyde coupling involved initial oxidative cyclization of the alkyne and the aldehyde to form a metallacyclic intermediate, followed by transmetalation (alkyl migration), βhydride elimination, and reductive elimination, as described in Scheme 17. With respect to regioselectivity, in 2010, Houk and co-workers showed that the selectivity of simple alkenes is controlled by steric effects,313 whereas for conjugated diynes or eneynes, the calculations (at the B3LYP/6-31G(d)(LANL2DZ) level of theory) suggested that the observed regioselectivity may originate from a mechanism involving a 1,4-attack pathway that is stabilized by a π-Ni interaction and has less distortion in the transition state (relative to other possible mechanism). A switch in regioselectivity of the coupling of alkynes and aldehydes was also observed when different sized carbene ligands were used.314 More specifically, by employing DFT calculations at the M06/6-311+G(d,p) (SDD)//B3LYP/6-31G(d)(LANL2DZ) level of theory, it was shown (as described in Scheme 18) that depending on the size, shape, and orientation of the ligand, different alkyne−aldehyde products could be obtained.

Figure 18. Assisted coordination of the Grignard reagent to the Ni complex by the hydroxyphosphine ligand.306

activation by ∼12 kcal/mol. Similar coordination effects of Grignard reagents to the Ni center were observed for fluoride anions in the NiF2-catalyzed Kumada coupling reaction.307 4.1.4. Negishi Coupling. The alkyl−alkyl Negishi coupling involving a Ni(I) complex was studied by X. Lin and Phillips in 2008.96 The calculations were performed at the PCM (THF) B3LYP/6-31G(d)(LANL2DZ) level of theory as the method was found, relative to experimental X-ray data, to perform well in reproducing the geometrical parameters of the investigated Ni complex.308 The computational study suggested a four-step Ni(I)/Ni(III) catalytic cycle involving iodine transfer, alkyl radical addition, reductive elimination, and transmetalation. The computational study suggested that the iodine transfer step may be the overall rate-determining step for the Ni(I)-catalyzed reaction with alkyl halides. A mechanism involving a transmetalation step between an alkyl−Ni(II)−iodide complex and RZnX was also tested but quickly discarded as it was shown to have a prohibitively high barrier. Similar conclusions were also observed for the coupling of aryl iodides with alkyl zinc reagents as that was also proposed take place via a Ni(I)/Ni(III) catalytic cycle.309 The rather facile oxidative addition of aryl iodide is proposed to occur directly to LNiI(alkyl) complex, as opposed to the stepwise addition of alkyl halides. In 2011, an enantioselective Negishi coupling of racemic secondary alkyl electrophiles was studied by X. Lin and coworkers at the PCM (DMSO)//B3LYP/6-31G(d) level of theory.310 Comparison of Ni(0)/Ni(II) and Ni(I)/Ni(III) pathways showed the latter to be more favored. The authors also showed that the enantioselectivity of the coupling is determined in the reductive elimination step, where the

4.2. C−H Bond Activation

Recent advances in Ni-catalyzed C−H bond activation reactions have triggered a number of computational studies focusing on their mechanistic details.125 Unlike Pd, which may have a variety R


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Scheme 17. Catalytic Cycle of the Ni-Catalyzed Alkyne− Aldehyde Coupling312

Figure 20. Selectivity switching in Ni-catalyzed hydroarylation of alkenes.315

Scheme 18. Ligand Size-Dependent Regioselectivity in NiCatalyzed Alkyne−Aldehyde Coupling314

[PivOCs·CsCO3)] cluster (Figure 21). The following C−H activation reaction of benzoxazole by that cluster is proposed to

of possible oxidation states involved in C−H functionalizations, Ni-catalyzed C−H functionalization reactions have so far predominantly been proposed to proceed via Ni(0)/Ni(II) pathways. In addition to the base-promoted concerted metalation deprotonation (CMD) mechanism, direct oxidative addition of the C−H bond to Ni(0) as well as ligand-to-ligand hydrogen transfer (LLHT), which resembles the σ-complexassisted metathesis (σ-CAM), are considered. For example in 2012, Shi and co-workers computationally explored a previously observed selectivity in Ni-catalyzed addition of heteroarenes to olefins that proceeds via C−H activation at the CPCM (hexane) B3LYP/6-311+G(2d,p)(SDD)//B3LYP/6-31G(d)(LANL2DZ) level of theory.315 The C−H activation was suggested to take place via oxidative addition of Ar−H to Ni(0).The alternative LLHT mechanism for C−H activation was suggested to proceed with a 7.6 kcal/mol higher barrier than the most favored oxidative addition pathway (ΔG‡OA = 14.9 kcal/mol). Thereafter an olefin can insert into the Ni−H bond, which, in case of alkyl-substituted alkenes, takes place in anti-Markovnikov fashion due to steric reasons (Figure 20). However, for aryl-substituted alkenes an additional secondary orbital overlap between Ni(0) and aryl ring allows the alkene to add in Markovnikov fashion. In 2014, Musaev and Itami studied the beneficial role of Cs2CO3 base in a Ni-catalyzed C−H/C−O biaryl coupling reaction of benzoxazole and naphthyl pivalate.316 A computational study, performed at the PCM (dioxane) M06/631G(d)(LANL2DZ) level of theory suggested that the carbonate base could, instead of performing a ligand exchange reaction with (dcype)Ni(Naph)(OPiv), also form a [(dcype)Ni(Naph)]-

Figure 21. Ni-catalyzed C−H/C−O biaryl coupling suggested to proceed via a Ni(II)·Cs2CO3 cluster.316

proceed with a lower activation barrier than any of the alternative pathways (Ni−pivalate or −carbonate complex). The results, which also included predicting reactivities of K2CO3 base and other heterocycles, are in an agreement with the presented experimental data. The performance of M06 and M06L was also compared in this study. Both methods were found to give very similar optimized geometries, with only subtle differences in relative energies. An alternative mechanism for C−H activation was found by Eisenstein and Perutz for Ni-catalyzed hydrofluoroarylation of alkynes.317 Disagreement between the predicted (at the B3PW91/6-31G(d,p)(SDD+f) level of theory) and the measured KIE values suggested the Ar−H oxidative addition pathway not to be preferred. Instead, calculations led to a proposal of a ligand-to-ligand H-transfer mechanism (LLHT) being operative (Figure 22a). The rate-determining step for this transformation was suggested to be the rotation of the vinyl group (trans−cis isomerization) on Ni. A similar ligand-to-ligand H-transfer mechanism was also proposed to be operative in a Ni-catalyzed Lewis acid-promoted dual C−H activation reaction, yielding a dihydropyridinone S


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4.3. C−O Bond Activation

Recent developments have made Ni catalysts also reactive toward unactivated C−O bonds, such as aryl alkoxides, esters, carbamates, and sulfamates. This unique reactivity has prompted many studies to understand and explain the mechanism and observed selectivities. In 2009, Liu et al. investigated this reactivity by studying the selectivity between O−Aryl and O−Acyl bond activation in aryl esters.321 In a system of phenyl acetate and (PCy3)2NiCl2 as a catalyst, only a biaryl product is observed after a reaction with an arylboronic acid derivative (Scheme 19). This finding is in Scheme 19. Slower but Irreversible Activation of the Ar−OAc Bond by Ni(PCy3)2 Leading to the Formation of the Observed Biaryl Product321 Figure 22. Ligand-to-ligand H-transfer mechanism (LLHT) being operative (a) in hydrofluoroarylation of alkynes317 and (b) in Nicatalyzed formation of dihydropyridinones.318

motif from a N,N-bis(1-phenylethyl)formamide and an alkyne (Figure 22b).318 Lewis acid (AlMe3), which coordinates to the oxygen of the formyl group, was shown to lower the barrier of the first C−H activation step (formyl C−H bond) by 14 to 23.2 kcal/ mol and the barrier of alkyne insertion by 11.4 kcal/mol. The alternative pathway, starting with C(sp3)−H activation was found to have a prohibitively high barrier of 42.7 kcal/mol, even in the presence of AlMe3. Moreover, the selectivity of a Ni-catalyzed Tishchenko reaction was assessed by Y. Fu and co-workers in 2012, who discovered that the previously proposed bis-carbonyl activation mechanisms fail to explain the observed high reactivity under experimental conditions319 (37 and 49 kcal/mol barriers for a reaction at 23−50 °C).320 Calculations at the CPCM (toluene) M06L/6-311+G(d,p)(SDD+f)//B3LYP/6-31G(d)(LANL2DZ) level of theory showed that an alternative monocarbonyl activation mechanism should be the most favorable (with a 19 kcal/mol barrier, Figure 23). The selectivity of the reaction was shown to result from the lowest absolute barrier of the C−H bond oxidative addition.

contrast to the bond dissociation energies (BDE) and activation energies of the two competing oxidative addition reactions, which suggest the formation of acetophenone. However, full assessment of the catalytic cycle (at the IEF-PCM (dioxane) B3PW91/6-311+G(2d,p)(SDD)//B3PW91/D95 V(d)(LANL2DZ+p,d,f) level of theory) suggested that the reversibility of the O−Acyl oxidative addition step and the high barrier of the transmetalation step allow only for the formation of biaryl product. In contrast to Pd(PCy3)2, which stays in a bisligated form throughout the catalytic cycle, the studied Ni(PCy3)2 was suggested to act as a monoligated catalyst since the barrier for bisligated oxidative addition was calculated to be a prohibitively high 54.9 kcal/mol. Furthermore, barriers toward oxidative addition of various Ph−X compounds (X = Hal, SAc, OSO2R, OR, NHAc) to Ni(0)PMe3 and Pd(0)PMe3 were compared, and in all cases lower barriers were obtained with Ni. A similar selectivity difference in (dcype)Ni-catalyzed coupling of phenol esters with azoles was studied in 2014 by Y. Fu and co-workers.322 In contrast to the initial mechanistic proposal by Itami,323,324 calculations at the SMD (dioxane) M06L/6-311+G(2d,p) (SDD+d,f)//B3LYP/6-31G(d) (LANL2DZ) level of theory indicated that in the case of decarbonylative coupling, the C−H activation step takes place before the CO migration (rate-determining step). If the CO migration would take place prior to C−H activation, the formed

Figure 23. Ni-catalyzed Tishchenko reaction. The previously proposed bis-carbonyl activation mechanism was proven to be not operative. The favored mono-carbonyl activation mechanism also explains the observed selectivity.320 T


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Ni(II) center would be too electron deficient to be able to engage in the C−H activation process. However, the calculated pathway for C−H/C−O coupling agrees with Itami’s initial proposal and indicates that initial C(phenyl)−O oxidative addition is followed by the rate-determining base-promoted C−H activation. With respect to chemoselectivity, the calculations showed that for bulky ester substituents the C−H/C−O coupling is preferred, whereas less bulky esters favored decarbonylative coupling. Furthermore, in 2012, Itami and co-workers found that the selectivity of C−O bond activation in aryl esters of aryl carboxylic acids can also be controlled by switching between PCy3 (Aryl−O activation) and dcype (Acyl−O activation) ligands (Scheme 20).323 Calculations from 2014 by Houk et al. at the SMD

Scheme 21. Ni-Catalyzed Coupling of Aryl Carbamates and Sulfamates326

Scheme 20. Ligand-Controlled Selectivity in Ni-Catalyzed Ar−OBz and ArO−Bz Bond Activation325

O−Amide and O−S bonds were found to have significantly higher barriers (17.4 and 16.1 kcal/mol, respectively). A different mechanism, compared to the standard Ni(0)/ Ni(II) cycle, was uncovered by Gómez-Bengoa and Martin in 2013, when joining the forces of computations (using the PCM (toluene) M06/6-311++G(d,p)(SDD)//B3LYP/6-31G(d)(LANL2DZ) methodology) and experiments to understand the Ni-catalyzed hydrogenation of Ar−OMe bonds.327 It was shown that the barrier for oxidative addition of Ar−OMe to Ni is 40.4 kcal/mol, thus ruling out the classical Ni(0)/Ni(II) catalytic cycle. Instead, Ni(I) intermediacy was suggested to be vital for the reaction (Scheme 22). The involvement of Ni−H species was

(dioxane) M06/6-311+G(d,p)(SDD)//B3LYP/6-31G(d) (SDD) level of theory suggest that the discrimination between these bonds by the two ligands stems from the different transition state structures (Scheme 20).325 The lack of a free coordination site in the case of a bidentate ligand only allows for a threecentered TS. Since the BDE of the O−Acyl bond is lower, this transition state is associated with a low distortion energy. In the case of monoligated PCy3, a free coordination site on Ni permits a five-centered transition state which can compensate for the added distortion energy via the buildup of additional interaction energy. In 2011, Garg, Snieckus, Houk, and co-workers used the ((PCy3) 2NiCl2) catalyst to couple aryl carbamates and sulfamates with arylboronic acids (Scheme 21).326 Computational studies at the CPCM (toluene)//B3LYP/6-31G(d) (LANL2DZ) level of theory were used to assess the higher reactivity of the sulfamates, the detrimental effect of water in the case of carbamates, and also the various potential transition states for the oxidative addition of Ar−O to Ni. The superior reactivity of sulfamates was found to result from its better leaving group ability, which shifts the resting state of the catalytic cycle to Ar− Ni−boronate complex as opposed to Ar−Ni−carbamate complex. This in turn lowers the barrier for the transmetalation step from 30 to 25 kcal/mol. In the case of carbamates, the presence of water forms an additional thermodynamic sink for the reaction when coordinated to the Ar−Ni−carbamate complex. In either case, a five-centered transition state is favored over the three-centered one (by 7−13 kcal/mol). The cleavage of

Scheme 22. Ni-Catalyzed Hydrogenation of the Ar−OMe Bond with Ni(I) Complex (Cy3P)2NiSiEt3 Being the Catalytically Active Intermediate327

ruled out due to the high stability of Ni−H dimers and the disagreement of the calculated mechanism with kinetic data. Lastly, a mechanism that is mediated by (Cy3P)2NiSiEt3 (Scheme 21) was taken into consideration and found to agree with all of the experimental data. U


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Controlling the selectivity in various cycloaddition reactions allows for quick access to desirably functionalized sophisticated ring systems.328−332 For example, Morokuma, Uchiyama and coworkers performed a computational study (at the M06/631+G(d)(LANL2DZ) level of theory) on the Ni-catalyzed [3 + 2 + 2] cycloaddition of cyclopropylideneacetate and two alkynes to determine how the nature of the reagents affects the outcome of the reaction (Scheme 23).333 Two different pathways were

and regioselectivities in the Ni-catalyzed cycloaddition of 3azetidinone with alkynes.343 Calculations performed at the CPCM (toluene) B3LYP/6-31G(d)//B3LYP/6-31G(d) (LANL2DZ+f) level of theory did not support the initially proposed oxidative coupling/β-carbon elimination mechanism (ΔG‡ = 46.5 kcal/mol).344 Instead, oxidative addition of the C(sp3)−C(O) bond of the azetidinone to Ni(0) was found to initiate the catalytic cycle (ΔG‡ = 26.8 kcal/mol), followed by the insertion of the alkyne and reductive elimination steps (Scheme 24). The authors also explained the different observed

Scheme 23. Substrate-Dependent Selectivity in the NiCatalyzed [3 + 2 + 2] Cycloaddition of Cyclopropylideneacetate and Two Terminal Alkynes333

Scheme 24. Ni-Catalyzed Cycloaddition of 3-Azetidinone with Alkynesa

suggested to be likely and leading to different isomers of cycloheptadiene, depending not only the bulkiness of the alkyne substituents but also on their electronic nature. Moreover, in their study, all possible transition states were located using the AFIR (artificial force induced reaction) methodology, which can be used to systematically search for transition states of multicomponent reactions.334−338 The mechanistic proposal of a Ni-catalyzed [4 + 4 + 2] cycloaddition reaction of a diyne and cyclobutanone by Murakami339 was computationally assessed by Chass and coworkers in 2012.340 Their results, obtained at the PCM (toluene) B3LYP/DZVP level of theory, showed that the reaction starts with the formation of Ni(0)−diyne complex, which leads to intramolecular C−C bond formation. Cyclobutanone then adds to this intermediate and forms a 7-membered Ni metallacycle. Lastly, β-carbon elimination and reductive elimination yield the [5−8] fused bicyclic product. In 2014, Houk, Louie, and co-workers investigated a Nicatalyzed cycloaddition of diynes and tropone which selectively affords [5−6−7] fused tricyclic products.341 Calculations at the CPCM (THF) M06/6-31+G(2d,p) (SDD)//B3LYP/6-31G(d) (SDD) level of theory suggest that the mechanism of the reaction consists of an unique 8π insertion of tropone to the metallacyclopentene intermediate which is shown to be 12.3 kcal/mol more favored than the traditional 2π insertion. Moreover, Houk and Baran elucidated the selectivity of Nicatalyzed [4 + 4 + 2] cycloaddition of dienes and alkynes at the M06/6-311+G(2d,p)(SDD)//B3LYP/6-31G(d)(SDD) level of theory.342 They showed that the E/Z selectivity is determined in the Ni-mediated oxidative cyclization of butadienes which is both kinetically and thermodynamically favorable only between s-cis and s-trans dienes. However, electron-deficient alkynes coordinate to Ni more strongly than the dienes and thus make the trimerization of alkynes the favored pathway. A study by Z. Lin and Li from 2013 evaluated the potential mechanisms (i.e., the oxidative coupling/β-carbon elimination pathway and the C(sp3)−C(O) oxidative addition mechanism)

a

The C(sp3)−C(O) oxidative addition pathway is shown to be favored over the initially proposed oxidative coupling/β-carbon elimination pathway.343

regioselectivities by noting that more electron-rich alkynes (e.g., MeCCtBu) act as nucleophiles and insert preferably into the Ni−C(O) bond, interacting with the more electron-deficient metal-bonded CO center and forming the intermediate II (Scheme 24). However, more electron-poor alkynes (e.g., Me−CC−TMS) act as electrophiles and insert into the Ni−C(sp3) bond to form the intermediate I (Scheme 24). Furthermore, a case of metal-dependent selectivity was studied in 2014 by Xie and Cao.345 Switching between Pd and Ni catalysts was shown to yield different outcomes in a reaction between cyclic anhydrides and alkynes (Figure 24). While Pd leads to the formation of a naphthalene ring upon stepwise extrusion of CO and CO2 and addition of two molecules of alkyne, Ni only promotes the initial decarbonylation and addition of one alkyne molecule, subsequently forming an isocoumarin derivative. Calculations performed at the CPCM (acetonitrile for Ni; DMF for Pd)//B3LYP/6-31G(d)(LANL2DZ+d,f) level of theory showed that different relative barriers for CO2 extrusion versus second alkyne insertion after an otherwise identical first part of the catalytic cycle are the reason behind this selectivity. V


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similar to CCSD, while M06 and the unusual HSE06351−356 were more similar to CCSD(T). Due to changes in electronic structures between different adducts there is a large systematic variation in the relative energies from DFT functionals. CASSCF calculations and T1 values indicated that to be the result of significant multireference character of the system caused by the dithiolene ligand. Due to insufficient description of Ni, the 631G(d,p) Pople basis set was found to perform poorly in energy calculations. Augmentation of cc-pVDZ or cc-pVTZ basis sets only led to minor improvements. Since aug-cc-pVDZ and 6-31+ +G(d,p) yielded similar results, the Pople basis set 6-31+ +G(d,p) was chosen as it gave a good compromise between time and accuracy. The authors also noted that geometry optimization was relatively insensitive to the choice of basis set or functional. In 2014, Xie and Xiong investigated the hydrosilylation of allenes, where the selectivity of the reaction is determined by the choice of metal (Pd or Ni) and ligand (1,3-bis(2,4,6trimethylphenyl)imidazol-2-ylidene (IMes) or 1,3-bis(2,6diisopropylphenyl)imidazol-2-ylidene (IPr)).357 The steric bulk of the ligand was found to determine whether the allene first is silylated (with bulky IPr) or hydrogenated (with IMes). Computational results obtained at the CPCM (THF)// B3LYP/6-31G(d)(LANL2DZ+d,f) level of theory indicated that Ni lowers the barriers for all reactions when compared to Pd (Scheme 26). The combination of Pd and IPr, which theoretically should give the vinylsilane product, however, has a prohibitively high barrier (40 kcal/mol).

Figure 24. Different reactivities in Pd- and Ni-catalyzed cycloaddition of an anhydride to alkyne. Pd promotes double addition via decarbonylation and decarboxylation, whereas Ni only promotes the initial decarbonylation and a single addition of an alkyne.345

4.5. Olefin Functionalization

In recent years several computational studies have investigated various Ni-catalyzed olefin functionalization reactions.346 For instance, in 2012, Hall and co-workers investigated the reaction between ethylene and nickel bis(dithiolene) complex Ni(tfd)2 (depicted in Scheme 25). Previously it was shown that

Scheme 26. Hydrosilylation of Allenes: Opposite Regioselectivities When Using Either Ni/IPr or Pd/IMes Systems357

Scheme 25. Addition of Olefin to the Nickel Bis(dithiolene) Complex and the Role of Catalytically Reduced Ni(tfd)2− in the Formation of a Stable Adduct348,349

The potential mechanisms of Ni-catalyzed reductive carboxylation of styrenes358 were computationally studied (at the PCM (THF) B3LYP/6-311+G(d) (LANL2DZ) level of theory) studied by Yuan and Z. Lin in 2014.359 The authors suggested that two competing mechanistic pathways existthe oxidative coupling mechanism and the nickel hydride mechanism. The former is proposed to generate an unproductive metallacyclic thermodynamic sink for the reaction. The nickel hydride mechanism, which consists of generating a Ni(II)−H species from ZnEt2 and Ni(0)−CO2 complex, subsequent olefin insertion to Ni−H bond, and reductive elimination, however results in successful catalytic turnover.

the presence of a reduced Ni complex Ni(tfd)2− can change the selectivity of the addition and determine whether a stable Ni adduct is formed.347 By combining kinetic and computational studies (using the SMD (CHCl3)//ωB97X-D/6-31++G(d,p) methodology) they uncovered a mechanism involving binuclear Ni complexes.348,349 Experiments first provided evidence for Ni(tfd)2−-catalyzed formation of the stable interligand adduct. Computational studies thereafter showed that a bimetallic intermediate is formed that binds the ethylene, followed by isomerization steps that lead more rapidly to the formation of a stable interligand adduct than to the unstable intraligand adduct. In a related study from 2012, Hall and co-workers assessed the performance of various DFT functionals in describing the energetics of the addition of ethylene to Ni(tfd)2 and the energies of different adducts.350 They found ωB97X-D to give results

5. RHODIUM Rhodium complexes are very versatile and popular catalysts for industrial hydrogenations and hydroformylations.360 Moreover, a broad range of Rh-catalyzed organic reactions exist, including further olefin functionalizations, conjugate additions, C−H and other bond activations, as well as transformations involving carbenes and cyclization reactions.361,362 Many mechanistic studies on Rh-catalyzed reactions employing DFT studies have been carried out since 2008 and will be discussed in the following sections. W


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5.1. Hydrogenation

showed that the highly enantioselective hydrogenation of MAC occurs via a dihydride pathway. The enantioselection occurs in coordination of the pro-chiral double bond in the octahedral Rh(III) intermediate. In contrast, DFT studies at the B3LYP/6-31G(d)(LANL2DZ) level of theory used by Reek and co-workers to rationalize experimentally observed enantioselectivity of Rh− IndolPhos-catalyzed asymmetric hydrogenation of olefins suggested an unsaturated pathway.376 It was found that only one of four possible diastereomeric catalyst−substrate complexes is accessible energetically, thus leading to observed selectivities. The same group also communicated the first dinuclear Rh catalyst for the hydrogenation of cyclic acetamidoalkenes.377 Their DFT calculations indicated that these novel complexes operate via a previously unknown cooperative hydrogenation activation mechanism displaying unusually high selectivities. The outer-sphere H bonding together with the dinuclear substrate activation shows similarities to the working principle of metalloenzymes and represents an activation mode previously unprecedented for Rh. Brodbelt, Baik, and Krische reported a combined experimental and computational study at the hydrogenative coupling of alkynes to carbonyl compounds and imines.378 The combined studies suggested the formation of a cationic rhodacyclopentadiene and subsequent insertion of CX (X = O, NSO2Ph). The following Brønsted acid-catalyzed hydrogenation of the formed intermediate was found to be rate determining and forms the C− C coupled product (Scheme 29).

While transfer hydrogenations are generally applied to polar double bonds (e.g., ketones and imines), classical hydrogenation using dihydrogen (H2) is mainly employed for olefins.361 From a mechanistic point of view, several proposals have been made regarding hydrogen transfer: (a) direct hydride transfer via the Meerwein−Ponndorf−Verley (MPV) reduction or (b) indirect transfer via metal hydride species (Scheme 27).363 For the latter, Scheme 27. Main Transition States Proposed for TransitionMetal-Catalyzed Hydrogenations: Scheme Displaying All Different Mechanismsa

a (a) Meerwein−Ponndorf−Verley (MPV), (b) Inner-Sphere, and (c) Outer-Sphere Pathways.

the formation of intermediate hydride species for both monoand dihydridic pathways have been considered. In the monohydridic process, both an inner-sphere mechanism (also called a migratory insertion mechanism with the substrate coordinating to the metal center) and an outer-sphere mechanism (without direct substrate coordination to the metal) have been suggested.364,365 Alternative to migratory insertion, σ-bond metathesis has also been considered in classical hydrogenation using H2.366 Since different proposals exist and are discussed with controversy, DFT calculations contributed to the unraveling of the mechanism on many occasions.364,365 5.1.1. Classical Hydrogenation. Enantioselectivity in Rhcatalyzed asymmetric hydrogenation was initially reported to originate from rate differences of oxidative addition of H2 to diastereomeric square-planar Rh(I) complexes.367,368 However, more recent mechanistic studies combining experiments with DFT calculations369−373 provide increasing evidence for a dihydride mechanism instead of the initially suggested unsaturated pathway (Scheme 28).374

Scheme 29. Rh-Catalyzed Hydrogenative Coupling of Alkynes to Carbonyl Compounds and Imines378

Scheme 28. Possible Mechanisms of Stereoselection in RhCatalyzed Asymmetric Hydrogenation

Similarly, Himo et al. investigated the mechanism and selectivity of Rh-catalyzed 1:2 coupling of aldehydes and allenes.379 On the basis of calculations at the CPCM (toluene) B3LYP/6-311+G(2d,2p)(LANL2DZ)//B3LYP/6-31G(d,p)(LANL2DZ) level of theory the initial oxidative coupling of the two allenes was shown to be the rate-determining step of the reaction. Moreover, the observed selectivities could be explained by a series of selection events throughout the catalytic cycle including oxidative coupling, β-hydride elimination, and reductive elimination. 5.1.2. Transfer Hydrogenation. In a recent study, Perutz and Eisenstein confirmed and explained previous experimental findings at the importance of two different substituents on the bis(amido) ligand of the CpRh(III) catalyst during transfer hydrogenation.380 B3PW91 calculations showed that the presence of two different amide substituents creates a good

In this context, Gridnev et al. investigated the Rh− ThangPHOS-catalyzed asymmetric hydrogenation of methyl (Z-α) acetylaminocinnamate (MAC) employing experimental NMR studies in combination with DFT computations at the CPCM (methanol) B3LYP/6-31+G(2d,2p)(SDD) level of theory.375 They compared previous mechanistic proposals and X


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related study, Morehead and Sargent investigated the mechanism of the intramolecular hydroacylation of olefins and reported a substrate-assisted reductive elimination that is critical to suppress both decarbonylation and catalyst deactivation pathways.384 In 2009, Woo and Dong studied the intramolecular hydroacylation of ketones to afford seven-membered lactones.385 Due to the lack of any spectroscopic evidence of reaction intermediates in these kind of transformations, the mechanistic investigations were complemented by computations at the B3LYP/LACV3P** level of theory. DFT calculations suggested that initial oxidative addition of Rh(I) into the aldehyde C−H bond is followed by insertion of ketone CO and reductive elimination to form a C−O bond. In agreement with experiments, ketone insertion was identified to be both rate limiting as well as enantiodiscriminating. Furthermore, decarbonylation was reported to be a competitive side reaction, which is highly dependent on the nature of the employed ligand. Ligands have been reported to have crucial effects on CO insertion. A recent example is a CO-induced methyl migration in a Rh−SCS pincer complex reported by Montag and Milstein (Scheme 31).386 In contrast to their previous studies on PCP and

bifunctional catalyst as it is bearing both an electrophilic Rh center for accepting H− and a nucleophilic NH group for coordinating H+ during the dehydrogenation of formic acid (Scheme 30). Scheme 30. Outer-Sphere Dehydrogenation of Formic Acid Catalyzed by Bifunctional 16e Rh Catalyst380

Furthermore, their study showed that observing an alkanoate species does not necessarily indicate an inner-sphere mechanism but rather is present as a catalyst resting state which is in equilibrium with the active species. DFT calculations showed a strong preference for an outer-sphere mechanism for the dehydrogenation of formic acid by CpRh(BsNC6H4NH) as well as an explanation for the better performance of catalysts bearing a saturated linker in the bis(amido) ligand. The latter could be explained by the lack of conjugation in the linking fragment which leads to a relief of built-in 4e− repulsion between the Rh and N lone pairs upon dehydrogenation of formic acid and thus to a lower energy barrier for saturated linkers compared to unsaturated linkers.

Scheme 31. Differences in Reactivity Between Rh−SCS (a) and PCP (b) Pincer Complexes386


5.2.1. Hydroformylation. One of the most important industrial processes for the functionalization of hydrocarbons is the selective hydroformylation. However, selectivity toward the desired linear products is still a topic of current research.381 In this context, Carvajal and Shaik conducted a detailed mechanistic study based on CPCM (toluene) B3LYP/6-31G(d)(SDD) and hybrid ONIOM calculations.381 They showed that large xanthene ligands favor η2-coordination of terminal olefins compared to internal olefins, thereby increasing the concentration of terminal alkene complexes leading to linear aldehyde products. However, the increased stability also makes the terminal olefin complexes less reactive. In a more recent study on the regioselectivity of hydroformylations, Kumar and Jackson employed dispersion-corrected DFT calculations to investigate the olefin insertion step on the Wilkinson catalytic cycle.382 While dispersion-corrected methods such as M06L and B3LYP-D3 were able to reproduce experimental regioselectivities, the commonly used B3LYP functional failed to do so. Thus, it was proposed that for an equatorial−equatorial arrangement of the phosphine ligands, transitions states leading to linear Rh−alkyl intermediates are stabilized by noncovalent π−π (ligand−ligand) and π-CH (ligand−substrate) interactions. 5.2.2. Hydroacylation. The development of intermolecular hydroacylation reactions has remained challenging due to the difficulty of suppressing the competing decarbonylation process. To avoid this problem, a 2-picoline-assisted intermolecular hydroiminoacylation was developed by Godard, Bo, and Castillón.383 On the basis of NMR experiments and DFT calculations, the inactivity of cationic Rh catalysts compared to active neutral Rh catalysts could be explained by a thermodynamically unfavorable oxidative addition. In a closely

PCN pincer complexes of Rh where the formation of an agostic C−C Rh(I) bond prevented the formation of a Rh acyl complex, its formation was facilitated by the use of a thiophosphoryl SCS pincer ligand. A comparative DFT study at the PBE0/PC1387(SDD) level of theory showed that the higher electrophilicity of the coordinating sulfur atoms of the SCS ligand decreases πbackdonation to CO and thus favors a methyl migration to CO. This is consistent with analysis of the oxidation state according to the quantum theory of atoms in molecules (QTAIM) which implies a Rh(V) oxidation state for SCS ligand but a Rh(III) oxidation state in the case of PCP ligand (Scheme 31). 5.2.3. Hydroaminomethylation. Hydroaminomethylation (HAM) is a tandem reaction to synthesize amines from alkenes (Scheme 32). After hydroformylation of the alkene, the obtained aldehyde is condensed with an amine and the corresponding imine or enamine is hydrogenated to yield an amine. Rhodium catalysts are very popular for this reaction sequence because they are able to catalyze both hydroformylation as well as enamine hydrogenation. However, careful catalyst optimization is a prerequisite so that the catalyst precursor can generate the corresponding required active species for both catalytic steps.388 Y


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Scheme 32. Hydroaminomethylation (HAM) Process

Scheme 33. Key Mechanistic Proposals for Rh-Catalyzed Hydrosilylation of Ketones by (a) Ojima,393,394 (b) Zheng and Chan,395 and (c) Hoffmann and Gade396,397

Recently, the groups of Urritigoiẗ y, Maron, and Kalck investigated the Rh−diphosphine-catalyzed hydrogenation of enamines in the HAM process in more detail and rationalized why this step lacks any enantioselectivity.389 The mechanism was explored by means of B97D/6-31G(d,p)(SDD) calculations to find that hydride migration from Rh to alkylamine is the ratedetermining step. The lack of enantioselectivity was shown to be a result of equal energies for both (E)- and (Z)-enamine pathways. In addition, calculations showed that employing a neutral Rh catalyst precursor is more efficient in generating the active species than the use of a cationic precursor. The same groups also conducted a combined experimental and computational mechanistic study of the HAM process, in which they reported an interplay of cationic and neutral Rh species.390 The CPCM (THF) B3PW91/6-31G(d,p)(SDD) calculations indicated an oxidative addition of H2 to cationic Rh species followed by deprotonation of the cationic dihydride complex by the amine. 5.2.4. Hydroamination. Although many intramolecular aminations of aminoalkenes and aminoalkynes have been developed, intermolecular hydroaminations are not as common. For example, the hydroamination of ethylene with ammonia, a reaction of particular interest for hydrocarbon functionalization, has been a long-standing challenge since all developed catalysts suffer from low activities.391 Thus, the groups of Hölscher and Leitner conducted a detailed computational study on Rh− pincer-catalyzed hydroamination of ethylene including an evaluation of different ligands and identification of detrimental side reactions.391 Their DFT calculation at the RI-PBE-D/def2TZVP level of theory identified a Rh−NCN pincer complex to be a promising catalyst and showed that oligomerization of ethylene is a partially competing pathway whereas the possible formation of diamides is clearly disfavored. 5.2.5. Hydrosilylation. Despite the extensive use of Rhcatalyzed hydrosilylation of ketones,392 only a few investigations on the mechanism of this transformation have been conducted. Thus far, two main mechanistic proposals have been made by Ojima393,394 as well as by Zheng and Chan (Scheme 33(a) and 33(b)).395 Although both proposals indicate the formation of Rh(III), the former is unable to explain the observed rate enhancement upon use of dihydrosilanes compared to monohydrosilanes as well as kinetic isotope effects and regioselectivities. Additionally, a new mechanism based on DFT calculations at the B3LYP/TZVP//BP86/SV(P) level of theory has been proposed more recently by Hoffmann and Gade,396,397 which involves the formation of a silylene intermediate (Scheme 33(c)). The presented mechanistic proposal can account for both the rate enhancement for secondary silanes as well as for the observed inverse kinetic isotope effect. 5.2.6. Hydroboration. Recently, Zeng and Takacs studied the carbonyl-directed Rh(I)-catalyzed hydroboration of a cyclic γ,δ-unsaturated amide.398 Their calculations at the PCM (THF)

B3LYP/6-311+G(d,p)(SDD)//B3LYP/6-31+G(d,p)(LANL2DZ) level of theory revealed detailed mechanistic insights which are also supported by experimental data. The preferred pathway was shown to proceed via a two-point chelation of the substrate using its carbonyl and its olefin moiety, followed by migratory insertion of the olefin into Rh−H bond, isomerization, and reductive elimination to form a B−C bond. In addition, a competing β-hydride elimination process was found that explains the observed minor formation of regioisomer. 5.3. Conjugate Addition

Rh−diene-catalyzed enantioselective 1,4-additions to enones are among the most widely used transition-metal-catalyzed asymmetric C−C bond forming transformations.399 Seminal DFT studies by Qin and Kantchev400−402 as well as by Brown and Hayashi 403 reported that the conjugate 1,4-addition is thermodynamically preferred over direct 1,2-addition. Moreover, carborhodation was identified as the enantiodetermining step in contrast to previous proposals on enone binding being enantiodiscriminating. Unexpected weak interactions between substrate and ligand were discovered, and it was suggested that enantioinduction occurs via selective distortion of the transition state. Due to their better description of weak interactions, hybrid meta-generalized gradient approximation (HM-GGA) functionals (i.e., MPWB1K) performed better in the calculation of activation barriers in comparison to hybrid GGA functionals (i.e., PBE0).402 In addition, a combined experimental and computational study on Rh−diene-catalyzed tandem 1,4-shift/1,4-addition to enones has been reported by Kantchev and Hayashi.404 Their PCM (dioxane) PBE0/DGDZVP level calculations showed that the 1,4-Rh shift occurs via an oxidative addition/reductive elimination sequence including a Rh(III) hydride intermediate. The barrier for carborhodation of the rearranged substrate proved to be significantly lower than that of unrearranged substrate, thus explaining experimentally observed selectivities. Z


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5.4. C−H Activation and Other Bond Activations

Scheme 35. Chemoselectivity in Rh(III)-Catalyzed Synthesis of Dihydroisoquinolone409

5.4.1. C−H Activation. Generally, mechanistic proposals for C−H activation can be divided into (a) inner-sphere or organometallic and (b) outer-sphere or coordination mechanisms.125 Follow-up reactions leading to C−H functionalization are numerous, and corresponding mechanisms do not necessarily depend on the C−H activation pathway.405 Inner-sphere pathways tend to activate less hindered C−H bonds due to the need for direct coordination on the crowded metal center. In contrast, outer-sphere pathways occur via reaction of a C−H bond with an activated ligand of the metal complex, a process which does not involve direct interaction of substrate with the metal center and thus favors activation of weak C−H bonds. To allow selective C−H bond activation, substrates containing directing groups such as carbonyls, amides, nitriles, and other heteroatom moieties have been used.406,407 These directing groups enable selective activation of one C−H bond over others by acting as a docking site for the catalyst metal center. Several mechanistic proposals regarding the activation of aromatic C−H bonds have been reported, including (a) Friedel− Crafts-type (SEAr), (b) Heck-type, (c) oxidative addition (OA), and (d) concerted metalation deprotonation (CMD) mechanisms (Scheme 34). In the case of Rh-catalyzed C−H activations, metalloradical pathways have also been reported.408

Scheme 36. Ligand-Controlled Selectivity in Rh(III)Catalyzed Dihydroisoquinolone Synthesis411

Scheme 34. Plausible Mechanisms for Aromatic C−H Activation Including (a) Electrophilic Aromatic Substitution (SEAr), (b) Heck Type, (c) Oxidative Addition (OA), and (d) Concerted Metalation Deprotonation (CMD)

in the cyclometalated Rh(III) intermediate determines selectivity. Recently, Chen and Z. Lin employed a similar hydrazinedirected C−H activation approach to synthesize indoles.412 Their calculations at the SMD (DCE) M06-D3/6-31G(d)// M06/6-31G(d) (LANL2DZ) level of theory showed that the combined process of CMD and alkyne insertion is rate determining. Furthermore, their calculations implied that using strong internal oxidant −NH(OAc) makes Rh(V) accessible, thereby facilitating a Rh(V)/Rh(III) pathway, whereas the reaction using weaker internal oxidant −NH(NHAc) follows a Rh(III)/Rh(I) cycle. The authors also explored potential basis set dependences and concluded that both small (6-31G(d) with LANL2DZ for Rh) and big (6-311+G(d,p) with SDD+f for Rh) basis sets give rise to the same relative stabilities of the key structures investigated. Goddard and Gunnoe recently reported an unprecedented long-range C−H activation, in which a benzylic C−H bond that resides six bonds away from the Rh center is activated (Scheme 37).413,414 DFT calculations suggest that the C−H activation proceeds via concerted metalation deprotonation of a dearomatized xylene intermediate. With respect to Rh-catalyzed propargylic C−H activation, Breit and co-workers recently carried out a mechanistic investigation by means of combined experimental and computational studies at the PCM (DCE) M06/def2-SVP//BP86/def2SVP level of theory.415 In contrast to their original mechanistic

In the context of Rh(III)-catalyzed aromatic C−H activation, Xia et al. conducted a detailed computational study on the role of internal oxidant.409,410 On the basis of computations at the PCM (MeOH) M06/6-311+G(d,p)(SDD)//M06/6-31G(d)(LANL2DZ) level of theory, divergent pathways of N-OMe and N-OPiv internal oxidants were studied and shown to proceed via N−H deprotonation, followed by C−H activation and olefin insertion. Divergency was suggested to result from different stabilities of the 7-membered rhodacycle intermediate. While this intermediate is unstable and undergoes β-hydride elimination and consecutive reductive elimination for N-OMe, the carbonyl oxygen of the N-OPiv can stabilize the rhodacycle such that the pivaloyl moiety is able to migrate to Rh. In the latter case, a cyclic Rh(V) nitrene intermediate is formed and reductive elimination to form a heterocycle is facilitated (Scheme 35). In a closely related study, Cramer and Corminboeuf reported regiodivergent pathways of Rh(III)-catalyzed dihydroisoquinolone synthesis that are controlled by the employed cyclopentadienyl ligand (Scheme 36).411 The differences between the employed catalysts were investigated by means of DFT calculations using the Amsterdam density functional (ADF) suite of programs and showed that the olefin coordination mode AA


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though the C−F bond is the strongest single bond to carbon its weakness lies in its polarity.427 Therefore, C−F bond activation is mainly achieved by nucleophilic attack and subsequent capture of fluoride by an electrophile (Scheme 39).428 A popular strategy is

Scheme 37. Long-Range Benzylic C−H Activation Reported by Goddard and Gunnoe413

Scheme 39. Possible Strategies for C−F Activation: (a) Formation of Organometallic Fluoride Complex, (b) Capture of Fluoride by an Electrophile (E), and the Corresponding Processes (c and d) with Concomitant Formation of RX (X = H, N, O, S) proposal of an oxidative addition of Rh into the O−H bond of the carboxylic acid,416 the present study suggests an unusual intramolecular protonation of the alkyne (Scheme 38). Scheme 38. Proposed Intramolecular Alkyne Protonation416

An allylic C−H activation assisted by conjugated dienes was studied by Z.-X. Yu et al.417,418 The mechanism was investigated via detailed DFT calculations at the CPCM (DCE) B3LYP/631G(d)(LANL2DZ) level of theory in order to understand the observed stereoselectivity as well as the role of the conjugated diene. The latter was shown to be critical for the reaction pathway as the diene disfavors double-bond isomerization and favors reductive elimination from Rh−bis-allyl complex to afford a cis-configured product. In a related study by Ujaque and Espinet, the originally proposed mechanism for the highly enantioselective Rh− BINAP-catalyzed asymmetric isomerization of allylamines to enamines was revised.419 On the basis of DFT calculations at the CPCM (acetone) B3LYP/6-31G(d,p)(LANL2DZ) level of theory, it was shown that, in contrast to previous suggestions, the nitrogen atom remains uncoordinated during the isomerization step. The novel mechanistic proposal includes Ncoordination of the allylamine, intramolecular isomerization to η2-coordination of the olefin followed by oxidative addition of C−H to form an allyl complex, and finally hydrogen transfer to form an enamine. Moreover, fluoroarenes allow for the activation of both C−H as well as C−F bonds. However, calculations have shown that barriers to oxidative addition of C−F are much higher than for C−H in the case of Rh catalysts,420 while for some Pt and Ni complexes C−F activation was favored.421−423 In this context, Jones et al. investigated C−H activation of fluoroarenes employing a [Tp′Rh(CNneopentyl)] catalyst.424,425 Their DFT calculations at the B3PW91/6-31G(d,p)(SDD) level of theory revealed a strong dependency of Rh−C bond strength on the number of ortho-fluorine substituents,426 while the total number of fluorines on the aromatic ring only resulted in minor differences. Experiments supported the computational findings and showed a strong preference for C−H activation on positions with the highest number of ortho-fluorine substituents. 5.4.2. C−F Activation. Although many synthetic methods deal with the incorporation of fluorine into organic molecules, the activation of C−F bonds is also of importance, since it allows for the selective functionalization of organic building blocks in positions that are otherwise difficult to functionalize.124 Even

the involvement of a ligand coordinated to a transition metal as a nucleophile.427 In this scenario the ligand is not just a spectator but is responsible for the nucleophilic addition to C−F, thereby forming a new C−X (X = H, N, O, S) bond. The departure of fluoride can be facilitated by either the metal center or the external electrophiles such as protons, silanes, or a lithium cation. While these electrophiles (E) form strong E−F bonds to capture fluoride also the much weaker hydrogen bonding proved to be of assistance in the departure of fluoride.429 In this regard, the groups of Macgregor and Braun studied the borylation of pentafluoropyridine catalyzed by a Rh(I) boryl complex.430 DFT calculations at the BP86/6-31G(d,p)(SDD) level of theory indicated a boryl-assisted pathway in which fluorine is directly transferred to boron via a four-membered transition state.431 Coordination of the pyridine N to Rh during the C−F activation process allows for a selective functionalization of pentafluoropyridine in the 2 position, a process that has been proven difficult to accomplish. In 2013, the same authors also reported a combined experimental and computational study on a similar silyl-assisted pathway for the activation of pentafluoropyridine at the 2 position.432 5.4.3. C−CN Activation. Selective cleavage of C−CN bonds over the more accessible C−H bonds has proven challenging.126,433 While Ni catalysts such as [NiH(dippe)]2 were reported to selectively activate C−CN over C−H,434 electronically similar Rh catalysts favor C−H activation. DFT analysis by Jones and co-workers indicated the presence of a high-energy intermediate bearing an agostic H interaction with Rh and connecting the transition states for C−H and C−CN activation (Scheme 40).435,436 While the barrier for C−H activation is lower, C−CN activation is favored thermodynamically. This finding is supported by experimental results, which report C−H activation via a photochemical reaction at room temperature but a thermal conversion to C−CN activation product upon prolonged heating. The same group also studied the effects of the employed ligands on selectivity of C−H versus C−CN bond activation.437 On the basis of DFT analysis at the PCM (MeCN) B3LYP/631G(d,p)(SDD) level of theory, the presence of σ-donating ligands such as phosphines was shown to be essential for AB


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5.5. Reactions of Rh Carbenoids and Nitrenoids

Scheme 40. C−CN versus C−H Activation: Interconversion Pathway through Intermediate with an Agostic H Interaction435,436 a

5.5.1. Rh Carbenoids. Transition-metal-catalyzed reactions of α-diazocarbonyl compounds are used in a vast number of valuable reactions including cyclopropanation, cyclopropenation, ylide-forming reactions, and insertions into heteroatom−H bonds.442−445 However, the scope of intermolecular reactions is severely limited due to competing β-hydride elimination. While intramolecular Rh-catalyzed reactions of α-diazocarbonyl compounds with primary or secondary alkyl substituents have been realized, intermolecular reactions proved to be more limited (Scheme 41). In the former cases β-hydride elimination could be Scheme 41. Reactivity of α-Diazocarbonyl Compounds: (a) Tendency To Undergo β-Hydride Migration and (b) Intramolecular versus Desired Intermolecular Reactivity446−448

a

Presented energies for L = Cp* and L = Tp (italicalized) were calculated at PCM (MeCN) B3LYP/6-31G(d,p)//(B3LYP/6-31G(d,p)(SDD+f) level of theory.

activation of C−CN bonds whereas π-acceptor ligands like isocycanides solely showed C−H activation. 5.4.4. C−O and O−O Activation. A competing C−H and C−O activation by a Rh β-diiminate complex was recently reported by Budzelaar and co-workers.438 DFT calculations showed that oxirane was opened via C−O activation, whereas dimethyloxirane reacted via methyl C−H activation because of steric hindrance in the C−O activation pathway. Furthermore, the high catalytic activity of Rh was attributed to the good stabilization and balance between Rh(I) and Rh(III) oxidation states. Moreover, Kennepohl and Crudden reported the reaction of a Rh−NHC complex with dioxygen without any change in oxidation state of the metal.439 DFT calculations suggested a novel type of bonding that can be described as an interaction of a square-planar Rh(I) complex with singlet oxygen (Figure 25), thus implying new possibilities in oxidation chemistry.

avoided in favor of the faster intramolecular reaction pathway. In contrast, very few reports on chemoselective reactions of αdiazocarbonyl compounds with β-tertiary alkyl substituents exist, and even intramolecular reactions proved to be difficult.446−448 In 2012, Fox and co-workers presented the first general intermolecular reactions of Rh−carbenoids bearing β-tertiary C−H bonds that are chemoselective over β-hydride elimination.449 Employing both low reaction temperatures and sterically demanding carboxylate ligands was essential to obtain chemoselectivity. DFT calculations at the B3LYP/6-311+G(d,p)(LANL2DZ) level of theory indicated that the rate of intermolecular reaction relative to β-hydride elimination is sensitive to the orientation of the carbonyl relative to the carbene. Employing cyclic α-diazocarbonyl compounds allowed for an increased conjugation of the carbene with the carbonyl group, which reduces steric interactions for intermolecular reactions and facilitates chemoselective reactions. In the same year, Musaev and Davies reported an enantioselective synthesis of allenes via a Rh-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between carbenoids and propargylic alcohols (Scheme 42).450 Computational studies at the PCM (n-pentane) M06L/6-311+G(d,p)(SDD) level of theory explained why the tandem reaction is favored over classical carbenoid insertion into the O−H bond when donor/acceptor carbenoids and highly functionalized propargylic alcohols are employed. Chemo- and enantioselectivity were attributed to an organized transition state involving two-point binding, in which ylide formation occurs between the carbenoid and the alcohol oxygen while the alcohol is hydrogen bonded to one of the carboxylate ligands. Moreover, a significant biradical character during [2,3]-sigmatropic rearrangement was

Figure 25. Novel bonding interaction between Rh(I) and singlet oxygen.439

5.4.5. N−H Activation. Recently, Chiou and co-workers presented the first example of a Rh-mediated oxidative cleavage of N−H bonds in the tandem hydrocarbonylation/cyclization reaction of homoallyl amines to form δ-lactams.440 On the basis of experiments and DFT calculations, the amine hydrogen was shown to serve as a hydride that participates in hydrocarbonylation and that the crucial Rh−H complex is formed via an intramolecular direct hydride transfer from N to Rh.441 AC


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(2d,2p)//B3LYP/6-31G(d)(SDD) level of theory and suggested that competing C−H bond insertion and CHCR reaction proceed through the same initial transition state via a potential energy bifurcation (Scheme 44).

Scheme 42. Enantioselective Synthesis of Allenes via a RhCatalyzed Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement of Carbenoids and Propargylic Alcohols450

Scheme 44. Hydride Transfer Transition State Leading to C− H Insertion and CHCR453

found, which explains why this reaction is favored for donor/ acceptor carbenoids and functionalized propargylic alcohols. In that context, the groups of Autschbach and Davies carried out a computational study on the selectivity of donor/acceptor Rh carbenoids showing that they are significantly more stabilized than conventional acceptor carbenoids.71 The donor group was suggested to provide an intrinsic higher stability, which leads to relatively late and partially charged transition states. Thus, donor/acceptor carbenoids show higher selectivities between substrates based on their electronic properties. The same authors also reported a Rh-catalyzed enantioselective cyclopropanation of electron-deficient alkenes.451 Remarkably, no ylide formation was observed in the case of acrylate substrate, although preferential reaction of the nucleophilic carbonyl oxygen with the electron-deficient carbene could be expected.452 DFT studies at the PCM (n-pentane) M06L/6311+G(d,p)(SDD) level of theory indicated the formation of a prereaction complex through weak interactions between the substrate carbonyl and the carbenoid. Depending on the nature of the unsaturated carbonyl compound different reaction pathways are preferred, leading to cyclopropanation of acrylates and acrylamides, whereas unsaturated aldehydes and ketones were epoxidized (Scheme 43).

Z.-X. Wang and X. Wang investigated the Rh-catalyzed hydroalkoxylation of alkynes by means of DFT calculations.454,455 This (Z)-selective anti-Markovnikov hydroalkoxylation of terminal alkynes catalyzed by Rh(I) was studied at the SMD (DMA) M06/6-311++G(2d,2p)//M06/6-31G(d)(SDD) level of theory. The detailed calculations indicated that the employed Rh−quinolato chelate catalyst not only directs substitution of phenylacetylene via a trans effect but also mediates hydrogen transfer through H bonding and allows for a differentiation of stereoselectivity-determining transition states via steric interactions with the chelate ligand. 5.5.2. Rh Nitrenoids. Rh nitrenoids have been found to be intermediates in C−H amination reations.456 In this context, Chang and co-workers investigated the Rh-catalyzed direct C−H amination reaction using azides as the nitrogen source.457 On the basis of a combined experimental and computational mechanistic study, the authors proposed that the reaction proceeds via a stepwise pathway involving a Rh(V)−nitrene intermediate. Their calculations at the iefPCM (DCE) B3LYP-D3/6-31G(d)//B3LYP/6-31G(d)(SDD) level of theory indicated that the stepwise pathway via the formation of a Rh(V)−nitrene intermediate is rate limiting and preferred over a concerted amide insertion pathway. Additionally, the final protodemetalation step was shown to occur via a CMD pathway. In a similar context, J. Li and co-workers studied the intramolecular C−H amination of biaryl azides catalyzed by late transition metals (Rh,458 Ir, Ru,459 Zn), theoretically employing DFT calculations at the B3LYP/6-31G (LANL2DZ) level of theory.460 Comparison of the four different transition metals showed that regardless of the metal a stepwise pathway including formation of a metal− nitrene intermediate via liberation of dinitrogen followed by C− N bond formation and concomitant 1,2-H shift. Aziridines are a common motif in natural products. However, their synthesis proved problematic and is mostly relying either on the generation of nitrenes by the use of strong external oxidants and their transfer to olefins or on the generation of carbenes followed by addition to imine CN bonds. Usually aziridines bearing protecting groups on N are obtained, and their deprotection is complicated by ring opening of the aziridine. Thus, the direct synthesis of unprotected aziridines represents a long-standing synthetic target.

Scheme 43. Cyclopropanation versus Epoxidation: Chemoselectivity of Rh−Carbenoids with Unsaturated Carbonyl Compounds451

Davies and co-workers investigated the tandem C−H activation/Cope rearrangement (CHCR) reaction between vinyldiazoacetates and allylic C−H bonds.453 Through a combined experimental and computational study, the mechanism was proposed to proceed via a concerted but highly asynchronous hydride transfer/C−C bond-forming reaction. The calculations were performed at the B3LYP/6-311+GAD


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Very recently, the research groups of Ess, Kürti, and Falck reported a direct stereospecific synthesis of unprotected N−H and N−Me aziridines from olefins catalyzed by dinuclear Rh(I).461 Computations at the CPCM (TFE) (U)M06/6-311+ +G(2d,2p)(LANL2TZ)//(U)M06/6-31G(d,p)(LANL2DZ) level of theory suggested that a catalytic pathway involving Rh− nitrene species is favored over corresponding Rh−amine and Rh−alkene catalytic cycles. Stereospecific aziridination was proposed to occur via generation of triplet Rh−nitrene, its reaction with olefin to form a first C−N bond via a triplet transition state, followed by spin interconversion to a singlet diradical. The second C−N bond was implied to form by thermoneutral coupling of the singlet diradical intermediate.

Scheme 46. Mechanistic Proposals of Rh-Catalyzed [5 + 2] Cycloaddition of 3-Acyloxy-1,4-enyne (ACE) with Alkynes468


5.6.1. [5 + 2] and [6 + 2] Cycloadditions. Seminal mechanistic work on vinylcyclopropane (VCP) cycloadditions based on DFT calculations has been carried out in the groups of Houk, Trost, Wender, and Z.-X. Yu.332,462−467 The proposed reaction pathway involves formation of a Rh−allyl complex, subsequent alkyne insertion into the Rh−allyl bond, leading to C−C bond formation with the terminal alkenyl carbon of the VCP, and final reductive elimination to afford a 7-membered ring (Scheme 45).

Rh(I)-catalyzed intermolecular [5 + 2] cycloadditions with VCPs.469 Computations at the CPCM (DCE) M06/6-311+G(d,p)//B3LYP/6-31G(d) (SDD) level of theory revealed an alternative allene dimerization pathway that becomes competitive when allene−ynes lack methyl substituents, thus explaining the apparent low reactivity of terminally unsubstituted allenes. Additionally, calculations suggested that the enhanced reactivity of terminal double bonds compared to internal double bonds is a result of more pronounced d−π* backdonation, whereas insertion of an internal double bond would break π conjugation. The closely related [6 + 2] cycloaddition of internal alkynes with cycloheptatriene was studied computationally by J. Wang and co-workers.470 On the basis of M06/6-31G(d)(LANL2DZ) calculations, a reaction mechanism including oxidative coupling of cycloheptatriene and internal alkyne, subsequent intramolecular migration of Rh(III)−C(sp3) bond, and final reductive elimination is proposed. The mechanistic proposal also accounts for the experimentally observed strong additive effect of CuI. A corresponding hetero-[5 + 2] cycloaddition reaction of cyclopropylimines and alkynes was studied mechanistically by Cabaleiro-Lago et al.471 Through DFT computations they were able to elucidate the differences between the Rh(I)-catalyzed reaction and its noncatalytic variant. While the latter is a two-step process with high activation barriers of 30.8 kcal/mol, a multistep process possessing lower barriers (14.9 kcal/mol, favored by 15.9 kcal/mol) was found for the Rh-catalyzed transformation. 5.6.2. [3 + 2] Cycloadditions. Z.-X. Yu and co-workers investigated the mechanism of Rh(I)-catalyzed intramolecular [3 + 2] cycloadditions of 1-ene- and 1-yne-VCPs by means of computations at the CPCM (DCE) B3LYP/6-31G(d)(LANL2DZ) level of theory.472 A mechanism involving cyclopropane cleavage, alkene or alkyne insertion, and reductive elimination was suggested in which the alkene or alkyne insertion is the rate- and stereoselectivity-determining step (Scheme 47). Moreover, insertion of alkynes proved to be more facile compared to alkenes, accounting for the experimentally observed higher reactivity of 1-yne-VCPs over 1-ene-VCPs. β-Hydride elimination was identified as a possible side reaction. However, this pathway can be inhibited completely by the use of a bidentate phosphine ligand. Following up on their mechanistic study, Z.-X. Yu et al. also established an asymmetric variant of the intramolecular [3 + 2] cycloaddition of 1-yne-VCPs that generates a chiral quaternary

Scheme 45. Proposed Mechanism of Rh-Catalyzed [5 + 2] Cycloaddition of Vinylcyclopropanes (VCP) with Alkynes332,462−467

The same groups previously presented a model for the prediction of regioselectivities based on CPCM (DCE) B3LYP/ 6-31G(d)(SDD) calculations.466 It was proposed that the steric bulk of the alkyne leads to a distal orientation in the alkyne insertion step, whereas electron-withdrawing substituents on the alkyne decrease or even reverse this selectivity leading to a proximal orientation. In the related Rh-catalyzed [5 + 2] cycloaddition of 3-acyloxy1,4-enyne (ACE) and alkynes, Houk, Xu, and Tang found a preferred insertion of the alkyne into a Rh−C(sp2) bond which governs regioselectivity (Scheme 46).468 This SMD (CHCl3) M06/6-311+G(d,p)//B3LYP/6-31G(d)(SDD)-based result is in contrast to [5 + 2] cycloadditions with VCP, where the alkyne is inserted into a Rh−allyl bond. The initial 1,2-acyloxy migration was found to be the rate-determining step of this transformation. Wender and Houk also reported a theoretical study on ligand effects in Rh(I)-catalyzed [5 + 2] cycloadditions.467 On the basis of dispersion-corrected B3LYP-D3/6-31G(d)(SDD) calculations, regioselectivities were attributed to unique steric and dispersion effects between ligand and substrate. Moreover, higher activities of bulkier ligands could be explained by steric repulsions that destabilize the catalyst resting state. Very recently, Wender and Houk reported a combined experimental and computational study on reactivity of allenes in AE


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Scheme 47. Mechanistic Proposal of Z.-X. Yu et al. for RhCatalyzed Intramolecular [3 + 2] Cycloadditions of 1-Eneand 1-Yne-VCPs472

Scheme 48. Pt(0)- versus Rh(I)-Catalyzed Asymmetric [4 + 1] Carbocyclization478

carbon center.473 DFT studies at the CPCM (DCE) M06/631G(d)//B3LYP/6-31G(d)(LANL2DZ) level of theory were employed to elucidate the origin of enantio-induction and showed that steric repulsion between the alkyne moiety and the BINAP ligand backbone is responsible for suppressing the less favored cycloaddition product. In a similar study, the same authors were able to rationalize the stereoselectivity of intramolecular Rh(I)-catalyzed, electronically neutral Diels− Alder reaction leading to cis-substituted bridgehead hydrogen atoms.474 5.6.3. [3 + 2 + 2] and [2 + 2 + 2] Cyclizations. Dang and Y. Fu conducted a systematic theoretical study of Rh(I)-catalyzed [3 + 2 + 2] carbocyclization reaction between alkenylidencyclopropanes (ACPs) and alkynes.475 The proposed alkene− carbometalation−first mechanism includes oxidative addition of the distal C−C bond of the cyclopropane, alkene carbometalation followed by alkyne carbometalation, and final reductive elimination, where the alkyne carbometalation step was found to be both rate and regioselectivity determining. In accordance with the experimental results of Evans and coworkers,476 steric crowding of the electron-withdrawing group on the alkyne governs regioselectivity in the alkyne carbometalation. Solà and Pla-Quintana recently reported the first DFT study on stereoselective Rh-catalyzed [2 + 2 + 2] cycloaddition of linear allene−ene/yne−allene compounds.477 Their investigations at the M06-2X/cc-pVTZ//B3LYP/cc-pVDZ level of theory rationalize in which order the different double/triple bonds react and provide an explanation for the observed diastereoselectivity. 5.6.4. [4 + 1] Cycloadditions. Very recently, Baik et al. presented an unprecedented switch in the enantioselectivity of [4 + 1] cycloadditions by changing the transition-metal catalyst.478 DFT calculations at the B3LYP/cc-pVTZ(LACV3P)//B3LYP/ 6-31G(d,p)(LACVP) level of theory provided new insights on the principles of inverting stereochemical preferences in asymmetric catalysis. Both mechanistic pathways of Pt(0)- and Rh(I)-catalyzed asymmetric [4 + 1] carbocyclization of vinylallenes with carbon monoxide were investigated (Scheme 48). The calculations suggest that in both cases the rate-determining step is the C−C coupling between vinyl carbon and carbon monoxide. However, the reason for enantiodiscrimination lies in the geometries of the metal centers adopted in the corresponding

transition states. While Pt maintains a square-planar orientation during C−C coupling, the coordination sphere of Rh is square pyramidal, thus leading to different steric influences and eventually to the formation of different enantiomers. 5.6.5. Ring-Opening Reactions. Rhodium has also been employed in ring-opening reactions with concomitant alkyne insertion by Murakami and co-workers.479 The experimentally observed site selectivity, which is opposite to that of a thermal ring opening, was studied computationally by Z. Lin and coworkers.480 Their calculations at the CPCM (toluene) M06/6311++G(d,p)//B3LYP/6-31G(d)(LANL2DZ) level of theory suggested that the reaction proceeds via β-carbon elimination followed by alcoholysis and alkyne insertion. The β-carbon elimination and alkyne insertion were shown to be site selectivity and regioselectivity determining, respectively. The calculations also showed that in the Rh-catalyzed reaction cleavage of the strained proximal C(sp2)−C(sp3) bond is preferred over cleavage of the distal C(sp3)−C(sp3) bond that is broken in the corresponding thermal reaction (without catalyst).

6. IRIDIUM In contrast to rhodium, for which most catalytic cycles are reported to occur on the Rh(I)/Rh(III) manifold, involvement of Ir(V) is often suggested in corresponding processes. Therefore, despite their many similarities and their use as catalysts for the same reactions, Ir offers several new possibilities and can achieve transformations that remain inaccessible for Rh.481 Thus, this section will not only highlight selected computational studies on Ir-catalyzed processes but also give attention to the differences to corresponding Rh-mediated transformations. 6.1. Hydrogenation

In contrast to Rh-catalyzed hydrogenation reactions, increasing evidence for involvement of Ir(III)/Ir(V) pathways482−485 has been reported in addition to “classical” Ir(I)/Ir(III) mechanisms.363,486−488 6.1.1. Classical Hydrogenation. Ke, Zhao, and co-workers recently conducted a mechanistic study on the hydrogenation of carbon dioxide providing new guidelines for the design of hydrogenation catalysts.489 Their calculations, performed at the B 3 L Y P / 6 -3 1 1 + + G ( d , p ) / / B 3 L Y P / 6 - 3 1 G ( d , p ) ( C E P 121G490−492) level of theory, indicated that the mechanism AF


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consists of two main steps: the heterolytic cleavage of H2 followed by hydride transfer. The latter was shown to proceed via a ligand-assisted outer-sphere mechanism. In addition, they could rationalize the higher catalytic activity of half-sandwich Ir complexes compared to their Rh and Co analogs. The higher activity of Ir was attributed to its increased ability to engage in d orbital back-donation in the rate-determining heterolytic cleavage of H2 (Scheme 49).

Scheme 50. Ir-Catalyzed Stepwise Hydrogenation of Quinolines via (a) Proton Delivery Followed by (b) Hydride Delivery495

Scheme 49. (a) Metal-to-Ligand Back-Donation Weakens Hydrogen Bond and Facilitates Hydrogen Cleavage via an Outer-Sphere Pathway; (b) Brønsted Acid-Assisted Hydride Transfer to CO2489

In addition, in 2010 Sicilia et al. reported a computational study of the Ir-catalyzed hydrogenation of O2 in which they showed that addition of H2 to Cp*Ir(TsDPEN−H) is favorable but slow and accelerated in the presence of Brønsted acids.497 However, the overall rate-determining step of this transformation appeared not to be the activation of H2 but the O2 insertion into the Ir−H bond, and calculated energetic barriers were in good agreement with experimental findings. In a similar Cp*Ir-catalyzed system, in 2011 Z.-X. Wang and co-workers reported a reversible dehydrogenation/hydrogenation of quinolines as a relevant reaction in hydrogen storage.498 On the basis of SMD (p-xylene) B3LYP/6-311+G(2d,2p)// B3LYP/6-31G(d,p)(LANL2DZ) calculations dehydrogenation/ hydrogenation was explained through a microscopically reversible process depending on the absence or presence of H2. In 2014, Brookhart, Krogh-Jespersen, and Goldman studied the hydrogenation of alkenes catalyzed by Ir−PNP pincer complexes.499,500 Their combined experimental and computational studies showed a remarkable difference to related hydrogenation employing isoelectronic Ir−PCP pincer complexes (Scheme 51). While the latter was reported to proceed via

On the contrary, Singh et al. reported a higher activity of Cp*Rh catalysts compared to their Ir analogs in transfer hydrogenation of ketones based on combined experimental and computational studies at the B3LYP/6-31G(d)(SDD) level of theory.493 In contrast to the aforementioned Cp*Ir-catalyzed hydrogenation of CO2,489 Morokuma and Nozaki presented a reversible hydrogenation of CO2 using an Ir−PNP pincer complex.494 Employing DFT studies at the PCM (H2O) B3LYP/ 6-31++G(d,p)(LANL2DZ) level of theory, two competing pathways, hydrogenolysis and deprotonative dearomatization, were suggested to be rate determining. This finding is in line with their experimental observations that both hydrogen pressure as well as base strength influenced the catalytic cycle and reaction equilibrium. In 2011, Crabtree and Eisenstein reported a combined experimental and computational study on the mechanism of the Ir-catalyzed hydrogenation of quinolines.495 Previously, this mild transformation has posed difficulties in rational design of catalysts as even closely related systems gave contradictory results in mechanistic studies.496 On the basis of B3PW91/631G(d,p)(SDDALL) calculations, Crabtree and Eisenstein proposed an unusual stepwise outer-sphere pathway, which involves sequential proton transfer from the coordinated H2, followed by hydride transfer from the obtained classical hydride complex (Scheme 50). The preferential binding of H2 to Ir compared to coordination of substrate was identified to be a crucial factor in the outersphere reaction pathway. This finding not only accounts for the higher activity of hindered substrates but also gives an explanation for the specific steric requirements of the employed ligand since the optimal ligand needs to be bulky enough to prevent coordination of substrate but not too bulky to maintain coordination of two ligands on the Ir center. Their conclusions provide further insights for the development of novel hydrogenation catalysts.

Scheme 51. Differences in σ-Donating Abilities of Pincer Ligands Cause Change in Preferred Oxidation State of the Metal and Hence Follow Different Reaction Pathways499

an Ir(III)/Ir(I)/Ir(III) catalytic cycle, this study strongly suggests an Ir(III)/Ir(V)/Ir(III) catalytic cycle for Ir PNP complexes.501 The DFT calculations at the M11/6-311G(d,p)(SDD) level of theory indicated a strong preference for Ir(III) compared to Ir(I), which was attributed to the poorer σ-donating ability of nitrogen in the PNP ligand in contrast to that of the AG


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6.1.2. Transfer Hydrogenation. In 2010, Lei et al. investigated the preferences of late transition-metal catalysts for molecular hydrogen as a hydrogen source in the hydrogenation of ketones.504,505 DFT calculations at the B3LYP/631+G(d,p)(LANL2DZ) level of theory suggest that 16e− Cp* complexes of Rh and Ir, which are efficient catalysts in transfer hydrogenation, can only activate H2 under acidic conditions as opposed to Noyori’s Ru catalysts (RuH2−diphosphine/diamine or Cp*Ru−diamine)506,507 which perform better in the activation of H2 than in transfer hydrogenation. The inability of typical Rh and Ir hydrogenation catalysts to activate H2 was attributed to their delocalized M−N π bonds which have to be broken in order to coordinate H2. However, addition of TfOH leads to the formation of a localized M−N π bond in the 16e− complexes and provides a vacant coordination site for the coordination and concomitant activation of H2 (Scheme 53).

coordinating carbon in the PCP pincer. Thus, Ir(III) to Ir(I) transformation is rendered thermodynamically inaccessible for the PNP pincer-supported catalyst system. Moreover, DFT analysis suggested that ethane elimination is promoted by H2 coordination and addition. This finding explains the inactivity of Ir PNP pincer complexes in transfer hydrogenation as no free H2 is present in the reaction mixture. This study provides new insights for the development of effective Rh(I)/Rh(III) catalysis since employing PNP pincer ligands may favor the previously insufficiently accessible Rh(III) oxidation state. Eisenstein and co-workers investigated the Cp*Ir-catalyzed Nalkylation of amines by alcohols.502 DFT calculations at the CPCM (toluene) B3PW91/6-31G(d,p)(SDD) level of theory suggested three key steps: (1) oxidation of the alcohol catalyzed by Ir, (2) nucleophilic addition of amine to aldehyde, and (3) Ircatalyzed reduction of the formed imine to afford a secondary amine. The first and last steps represent mirroring reaction pathways since Ir needs to both oxidize an alcohol and also reduce an imine. The carbonate ligand proved to be essential for facilitating both reactions as it can act as a “proton shuttle”. Product formation was shown to be a result of both more facile hydrogenation of imine compared to aldehyde as well as preferred oxidation of alcohol over amine. Norrby, Diéguez, Rasmussen, and Andersson developed a model for the prediction of enantioselectivities in Ir-catalyzed hydrogenation of olefins based on a mechanistic DFT study.482,483 Their calculations revealed an Ir(III)/Ir(V) catalytic cycle in which migratory insertion of a hydride is selectivity determining. The effect of both ligand modification as well as enantioselectivity could be rationalized using a quadrant model. Similar to their studies on related Rh-catalyzed systems, Gridnev and W. Zhang also proposed a dihydride pathway for Ir−BiphPhox-catalyzed hydrogenation of exocyclic α,β-unsaturated carbonyl compounds.488 On the basis of DFT studies, migratory insertion was suggested to be the enantiodetermining step. However, the involvement of an Ir(III)/Ir(V) catalytic cycle could not be unambiguously confirmed. In 2010, Burgess et al. were able to show that asymmetric hydrogenations of alkenes are sensitive to protons generated in the reaction.503 Their DFT studies at the CPCM (DCM) TPSS/ 6-31G(d) level of theory indicated strong differences in the acidity of the chiral Ir hydrogenation catalysts (Scheme 52). In

Scheme 53. (a) Noyori’s Ru-Catalyzed Hydrogenation;506,507 (b) Late Transition-Metal Catalysts Commonly Employed for Transfer Hydrogenation Can Activate H2 Only under Acidic Conditions504

In this context, Dahlenburg and Clark reported a cationic hydridoiridium(III) complex bearing a β-aminophosphine ligand,508 which favored transfer hydrogenation over activation of H2, although the complex is similar in structure to the efficient hydrogenation catalyst RuH2−diphosphine/diamine complex. On the basis of B3LYP/LANL2DZp calculations the authors suggested that the lack of activity toward H2 can be attributed to the inability of H2 to displace a coordinated solvent molecule in the cationic Ir system. Recently, the groups of Baya and Mata reported a novel Cp*Ir catalyst bearing an NHC ligand and a cyclometalated primary benzylamine which proved to be highly active in transfer hydrogenation of ketones at low temperatures.365 SMD (iPrOH) M06/6-31G(d,p)(SDD)-based DFT studies suggested a concerted, one-step, outer-sphere hydrogenation mechanism similar to Noyori’s Ru-catalyzed transfer hydrogenation (Figure 26). 6.1.3. Dehydrogenation. Sunoj et al. studied the Ir PCPpincer-catalyzed dehydrogenation reaction of n-hexane to afford benzene through DFT calculations at the M06/6-311+G(d,p)(SDD)//B3LYP/6-31G(d,p)(LANL2DZ).509 Six important steps of the catalytic cycle were reported, involving hydrogenation of tert-butylethylene employed as a sacrificial acceptor,

Scheme 52. Acidity of Ligands Effects Catalytic Abilities of Ir in Asymmetric Alkene Hydrogenation503

combination with experiments it was shown that an exchange of phosphine-based ligands by carbenes significantly lowered the acidity of the corresponding Ir complexes resulting not only in more effective hydrogenation of acid-sensitive alkenes but also diminished acid-mediated alkene isomerization. Thus, it was proposed that the catalytic abilities of many transition-metal hydrides could drastically change upon phosphine to carbene ligand exchange. AH


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Scheme 54. Formation of Active Ir Catalyst That Governs Regio- and Enantioselectivity via C(sp2)−H Activation522

Figure 26. Concerted, one-step, outer-sphere hydrogenation proposed by Baya and Mata.365

sequential formation of dehydrogenated intermediates hexane, hexadiene, and hexatriene, and electrocyclization of the triene to afford cyclohexadiene, which is then converted to benzene via a final dehydroaromatization.

authors found that geometry optimizations employing the M062X method could reproduce X-ray structures best as opposed to other tested methods including B3LYP, BP86, and M06.


6.4. C−H Bond Activation and Other Bond Activations

6.2.1. Hydroamination. Only a few Ir-catalyzed hydroaminations have been reported, and very little is known about their mechanistic pathways.510 In 2010, Tobisch and Stradiotto reported an Ir(I)-catalyzed intramolecular hydroamination of unactivated olefins with primary and secondary amines.511,512 On the basis of a combined experimental and computational study at the TPSS/TZVP(SDD) level of theory, an unprecedented electrophilic activation of the olefin by the electrondeficient Ir center is proposed, which is succeeded by reversible ring closure via nucleophilic attack of the amine moiety on Ir. The Ir−C bond in the obtained zwitterionic intermediate was shown to be cleaved via stepwise proton transfer from ammonium to Ir and subsequent reductive elimination, which represents the turnover-limiting step of the reaction. An alternative N−H activation mechanism, which is usually encountered in electron-rich Ir systems, was excluded due to an energetically inaccessible N−H activation via oxidative addition to Ir(I).

6.4.1. C−H Activation. Many different mechanisms have been proposed for the Ir-mediated C−H activation (Scheme 55),36,125,523−527 among them are (a) oxidative addition, (b) σScheme 55. Mechanistic Proposals for Ir-Catalyzed C−H Activation Including (a) Oxidative Addition (OA), (b) σBond Metathesis (σ-BM), and (c) Ambiphilic Metal Ligand Activation via 4- (σ-CAM) and 6-Membered (CMD) Transition States

bond metathesis, and (c) ambiphilic metal ligand activation (AMLA) via 4-membered (also termed σ-complex assisted metathesis, σ-CAM) or 6-membered transition states (equal to concerted metalation−deprotonation, CMD). Support for the involvement of metalloradical pathways is scarce. For instance, Balcells, Crabtree, and Eisenstein reported that in the stereoretentive C−H hydroxylation of cis-decalin a direct oxygen insertion pathway is favored over radical rebound mechanism.528 Gorelsky and Woo investigated the Ir(III)-catalyzed direct arylation of various heteroarenes employing DFT calculations at the PCM (toluene) B3LYP/TZVP(LANL2DZ) level of theory.529 CMD was found to be favored over the previously suggested SEAr mechanism.530 Moreover, ligands with low trans effects were found to lower activation barriers for C−H activation. The influences of various ligands on the C−H activation process have been studied. For instance, Goldberg and Cundari investigated the effect of ancillary ligands on CMD mediated by (dmPhebox)Ir(OAc)2(H2O) (Scheme 56).531 The C−H activation of alkanes via CMD was studied by means of computations at the PBE0/6-311G(d,p)(SDD) level of theory. While substitutions on the aryl moiety or the oxazolinyl pincer arms only had minor impact, the base and spectator ligands were found to significantly influence the barrier of activation toward C−H activation due to their basicity as well as their trans influence/effect.532 Thus, employing heteroaryl pincer back-

6.3. Allylic Substitution

Ir-catalyzed allylic substitutions, first reported as Pd-catalyzed reactions by Tsuji513 and Trost,514 are widely used and reliable synthetic methods.515 Asymmetric Ir-catalyzed versions have been developed by Helmchen employing a chiral phosphinooxazoline ligand516 and Hartwig using a phosphoramidite ligand.517 Experimental mechanistic studies by Hartwig and co-workers showed that enantioselecitivity is a result of selective oxidative addition under Curtin−Hammet conditions and proceeds via a double-inversion pathway.518−520 In this regard, Helmchen et al. performed a detailed mechanistic study of asymmetric allylic substitutions catalyzed by cyclometalated Ir−phosphoramidite complexes.521 Employing a combination of experiments and DFT calculations, it was suggested that observed regioselectivities are not a result of relative stabilities of product olefin complexes, since complexes of branched products were found to be less stable as their linear analogs, although formation of branched products is predominant. You and co-workers investigated an allylic alkylation reaction mediated by an Ir catalyst bearing N-aryl phosphoramidite ligands.522 DFT calculations at the SMD (THF) M06-2X/631G(d,p)(SDD) level of theory indicated that the active π-allyl iridacycle that governs regio- and enantioselectivity is formed via C(sp2)−H bond activation (Scheme 54). Interestingly, the AI


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to be favored. The mechanistic proposal includes η1-allyl formation from the η2-olefin, C−H activation at the η1-allyl to afford an η1-allyl hydride, followed by closing to yield an η3-allyl hydride (Scheme 57). Isomerization was suggested to occur via an η1-η3-η1 sequence, formally a 1,3-Ir shift, and not via the previously proposed hydride addition pathway.539

Scheme 56. Summary of Calculated Ligand Effects on Ir Oxazolinyl Pincer-Catalyzed C−H Activation of Methane via a Concerted Metalation Deprotonation (CMD) Pathway531

Scheme 57. Ir-Catalyzed Olefin Isomerization via C−H Activation and Formal 1,3-Ir Shift (η1-η3-η1 coordination of the allyl moiety)538

bones might facilitate C−H activation by increasing the electrophilicity of the cationic Ir center. In a related study, Bera and co-workers observed COD activation by an Ir(III)−NHC complex.533 In a DFT study at the B3LYP/6-31+G(d,p)(LANL2DZ) level of theory, it was shown that the presence of an acetate ligand is essential for the allylic C− H activation of COD. These findings raise questions about the innocence of COD ligands in organometallic reactions, in particular in the presence of metal-bound acetates. In a combined experimental and computational study Heinekey et al. showed that an oxidative addition mechanism is favored for the C−H activation by a cationic Cp*Ir(III). They also elucidated that exchanging the employed phosphine ligand by a more sterically encumbered NHC ligand had a detrimental effect on the rate of C−H activation.534 Bera and co-workers also found a carbon monoxide induced double cyclometalation of 2-phenyl-1,8-naphthyridine ligands on Ir.535 DFT studies revealed that the first cyclometalation takes place via an oxidative addition, while the second cyclometalation is a result of subsequent electrophilic activation and elimination of H2. Interestingly, in contrast to its usual role in preventing oxidative addition by lowering electron density on the metal center, CO acts as a promoter of oxidative addition in this study. Krogh-Jespersen and Goldman recently reported the activation of C−H as well as C−C bonds by Ir−PCP pincer complexes.536 On the basis of experiments and DFT calculations they showed that Ir bearing sterically crowded pincer ligands undergoes selective addition to C−H of biphenylene. Upon heating, the formed complex is however converted to the formal C−C addition product. Using a less sterically encumbered pincer ligand afforded direct C−C addition. The difference in the ligands could be explained by the nature of the C−C addition transition state, in which an out of plane tilt causes strong substrate ligand interactions and is thus only feasible for less sterically hindered ligands. These findings provide novel insights toward the activation of unstrained aryl−aryl bonds. Hall and co-workers computationally explored the selectivity of C−H versus C−Cl oxidative addition of chlorobenzene by an Ir(I)−PNP pincer complex.537 C−H activation was found to be kinetically favored but can be converted to the thermodynamically preferred C−Cl addition product via an intramolecular reaction through a benzyne (η2) intermediate. Brookhart, Krogh-Jespersen, and Goldman investigated the Ir−PCP pincer-catalyzed olefin isomerization by means of a combined experimental and DFT study at the PBE/6-311G(d,p)(LANL2TZ) level of theory.538 Surprisingly, a direct C−H activation pathway via an allylic σ-complex (η1-allyl) was found

Very recently, Krogh-Jespersen and Goldman studied the acidcatalyzed oxidative C−H bond addition to square-planar Ir(I) complexes.540 While addition of C−H bonds to three-coordinate Ir(I) species is well known, the corresponding addition to fourcoordinate complexes is rare. Combined kinetic studies and DFT calculations at the CPCM (chlorobenzene) M06/6-31+G(d,p)(LANL2TZ,6-311+G(d,p)) level of theory suggest protonation of Ir−PCP complex to form highly active five-coordinate cationic Ir(III), which electrophilically adds to phenylacetylene, followed by rate-determining deprotonation and concomitant formation of trans C−H addition product. Similarly, Milstein and co-workers reported the C−H activation of acetone on a square-planar Ir−PNP platform via a reversible ligand dearomatization (Scheme 58).541 DFT Scheme 58. Milstein’s PNP Pincer System: C−H Activation by Dearomatized Ligand Scaffold541

calculations showed that the C−H bond is activated directly by the dearomatized PNP ligand scaffold, highlighting the crucial role of metal−ligand cooperation via aromatization/dearomatization.542 In analogy to the Rh(III)-catalyzed dihydroisoquinolone synthesis (see Rh-catalyzed C−H activation), Ison and coworkers reported an Ir(III)-catalyzed oxidative coupling of benzoic acids with alkynes to form isocoumarins.543 In contrast to the former reaction that employed N-OPiv as an internal AJ


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oxidant, AgOAc was required as an external oxidant in the latter process. On the basis of DFT calculations at the SMD (methanol) BP86/6-31G(d,p)(SDD, LANL2DZ) level of theory, a mechanism including C−H activation via CMD followed by alkyne insertion and oxyfunctionalization accompanied by catalyst regeneration by the oxidant was proposed. In opposition to a previous proposal,544 alkyne insertion instead of C−H activation was found to be the rate-determining step of the process. In the related metallacycle formation via C−H activation of phenyl imines, W. Zheng et al. investigated the differences between Rh and Ir catalysts.545,546 On the basis of DFT computations at the PCM (methanol) B3LYP/6-31G(d,p)(LANL2DZ) level of theory, the higher reactivity of Ir compared to Rh was attributed to its higher electrophilicity which facilitates C−H activation both kinetically as well as thermodynamically. Goddard and Periana reported an Ir-catalyzed H/D exchange between water and benzene in the presence of base.547 DFT calculations at the B3LYP/LACV3P++**//B3LYP/LACVP** level of theory suggest that the dihydroxo Ir(III) pyridyl complex is activated by loss of pyridine, which facilitates heterolytic C−H activation of benzene via an ambiphilic substitution transition state. The two hydroxo ligands are essential for the observed reactivity as they make the Ir complex water soluble. Similarly, Goldberg, Jones, and co-workers investigated the H/ D exchange reaction of arenes with trifluoroacetic acid catalyzed by Rh and Ir complexes bearing a fac-chelating ligand bis(3,5dimethylpyrazol-1-yl)acetate (bdmpza).548,549 DFT calculations at the B3LYP/6-31G(d,p)(SDD) level of theory suggested an η1CH arene coordination and subsequent base-assisted (concerted metalation deprotonation) C−H activation pathway. 6.4.2. C−F Activation. A range of different strategies have been pursued in order to activate the strong C−F bond, including ligand-assisted activation pathways.550 For example, Macgregor and co-workers proposed a phosphine-assisted C−F activation pathway for the reaction of hexafluorobenzene with [IrMe(PEt3)3].551 On the basis of a DFT study at the PCM (benzene) BP86/6-31G(d,p)(SDD) level of theory, this novel mechanism was suggested to proceed via a 4-centered transition state that formally involves nucleophilic attack of electron-rich Ir and trapping of displaced fluoride by the phosphine ligand (Figure 27). After initial formation of an iridaphosphorane, ethyl transfer

Scheme 59. Initial C−H Activation Leading to C−F Activation552

6.4.3. C−O Activation. Krogh-Jespersen and Goldman also investigated the C(sp3)−O activation reactions of ethers, esters, and tosylates by an Ir−PCP pincer complex.553 Similarly to their C−F activation mentioned above (see section 6.4.2), reactions were shown to occur via an initial C−H bond activation and sequential α-OR migration (OR = OAr, OTs, OAc, or OC(O)Ar) rather than via direct C−O addition (Scheme 60). Scheme 60. Ir-Catalyzed C−O Activation via Initial C−H Activation553

DFT studies also indicated that substrates bearing β-C−H bonds undergo 1,2-dehydro-oxygenation to afford olefins, while C−O cleavage in acetates was found to occur in an unprecedented sixmembered transition state without direct involvement of Ir. In 2014, catalytic C−O bond cleavage based on this study has been presented by the same group.554 The novel insights gained in this study may, according to the principle of microscopic reversibility, also be applied to C−O bond formation as shown by Krogh-Jespersen and Goldman in the Ir−PCP-catalyzed olefin hydroaryloxylation.555 DFT studies have excluded the usual “hidden Brønsted acid” mechanism proposed for similar catalytic systems556,557 and suggested an olefin insertion into Ir−O bond, followed by the ratedetermining C−H elimination to afford the ether product. This highly chemo- and regioselective transformation represents an atom-economical alternative to the classical Williamson ether synthesis. A similar intermolecular hydroetherification of unactivated aliphatic olefins catalyzed by Ir−Segphos has been reported by Hartwig et al.558

Figure 27. Ir-catalyzed phosphine-assisted C−F activation.551

from P to Ir affords the observed product. Alternative pathways such as oxidative addition or electron transfer to yield an Ir(III) fluoride complex were shown to be energetically disfavored. On the other hand, Krogh-Jespersen and Goldman reported an unusual pathway for the Ir−PCP-mediated activation of C(sp3)−F bonds.552 DFT calculations showed that a direct C−F oxidative addition is energetically unavailable, and the preferred mechanistic pathway involves an initial C−H activation, followed by an α-fluorine migration and hydride migration to afford the formal C−F addition product (Scheme 59). Alkyl fluorides possessing β-hydrogen atoms were found to undergo dehydrofluorination yielding olefins. The latter reaction was proposed to proceed via C−H oxidative addition and subsequent β-fluoride elimination to afford the olefin. AK


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6.4.4. Borylation. In 2013, Y. Fu and co-workers carried out a detailed computational study559 on the mechanism of Chatani’s Rh- and Ir-catalyzed borylation of nitriles.560 DFT calculations at the SMD (toluene) M06/6-311G(2d,p)(SDD)//B3LYP/631G(d)(LANL2DZ) level of theory revealed that the initially proposed unconventional β-carbon elimination mechanism was disfavored and that a deinsertion pathway is preferred. The latter mechanistic pathway was shown to occur via 2,1-insertion of M− B into the CN triple bond, followed by an insertion of the metal center into the C−CN bond. This C−CN bond activation proved to be facile and the subsequent oxidative addition of diboron reagent to be rate-determining. Overall, the Rhcatalyzed pathway possessed slightly lower activation barriers than the corresponding Ir-catalyzed process.561 In a related study in 2014, Merlic, Houk, and co-workers investigated the borylation of substituted arenes and heterocycles.562 Their computations at the SMD (n-octane) M06/6311G(d,p)(SDD)//B3LYP/6-31G(d)(LANL2DZ) level of theory suggested that C−H oxidative addition transition states are very late and in close resemblance to the aryl Ir hydride intermediate. Thus, regioselectivity is mainly interaction energy controlled.

Figure 28. Ir-catalyzed intramolecular [5 + 2] cycloaddition of vinylcyclopropanes with alkynes.568

catalyzed system. In addition, experiments have shown an increased functional group tolerance and up to quantitative yields for this novel cationic Ir catalysis. Thus, these findings should encourage investigations in the field of Ir catalysis and might help to improve catalytic processes previously carried out under Rh catalysis.

7. CONCLUSION AND OUTLOOK With ever-increasing computational power and improvements in computational methodology, computational chemistry has evolved into a powerful tool that can be used to study, rationalize, and even predict organometallic reactivity. Currently, B3LYP is still the preferred choice for geometry optimization, but for energy calculations, methods, that better account for dispersion, such as M06 and DFT-D3, are becoming increasingly popular because of their ability to provide a better quantitative description of reaction energies and activation barriers. Most calculations that have been reviewed herein (involving Pd, Ni, Rh, and Ir) have been predominantly conducted postexperimentally to rationalize the chemical reactivity observed. However, we hope that this review convincingly showcased the power and opportunities of implementing computational tools not only in the study but also in the development of reactions. Currently, there is arguably an underexplored potential of utilizing computational chemistry in the development of innovative synthetic concepts. We hope that this review will stimulate more pre-experimental applications as well as combined experimental/computational approaches and that computational chemistry will feature more prominently in future reaction developments.

6.5. Reactions of Ir Carbenoids

Carmona et al. considered Ir−carbene intermediates in C−H activation reactions and described the unusual reactivity of a cationic Cp*Ir(III) complex bearing a bis(aryl)phosphine ligand.563 In a combined experimental and DFT study at the SMD (DCM) M06/6-31G(d,p)(SDD) level of theory it was shown that the Ir(III) complex undergoes intramolecular benzylic C−H activation with the aryl moieties of the phosphine ligand, which was suggested to occur via an Ir(V) hydride intermediate. The formed highly electrophilic cationic Ir(III) alkylidene was shown to undergo intramolecular C−C coupling to afford a hydride phosphepine complex. In this context, Yates and co-workers investigated the factors that influence carbene formation564 versus vinyl ether adduct formation at an Ir−PNP pincer complex as observed in the reaction of linear and cyclic ethers with Ir−PNP.565−567 DFT calculations at the B3LYP/6-311+G(2d,p)(LANL2TZ +)//B3LYP/6-31G(d)(LANL2DZ) level of theory suggest that only carbon atoms that reside α to the ether oxygen are accessible for carbene formation because π backdonation from Ir to carbene is feasible. Otherwise, vinyl ether formation via C−H activation/β-hydride elimination occurs, unless the ether substrate is sterically hindered, in which case the intermediate is trapped after the initial C−H activation. These findings give further insights to understand the broad range of products including carbenes, vinyl ethers, as well as decarbonylation products that are observed in the Ir−PNP-catalyzed C−H activation of linear and cyclic ethers.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies


Very recently, Strand and co-workers reported the first Ircatalyzed inter- and intramolecular [5 + 2] cycloadditions of vinylcyclopropanes and alkynes (Figure 28).568 Previously, these transformations were primarily carried out under Rh,569 Ni,570 Ru,571 or Fe572 catalysis. Strand et al. were able to show that their cationic Ir catalyst exhibited a substantial increase in reaction rate compared to Rh. DFT calculations at the PBF(DCE) M06-2X/ LACVP** level of theory imply that the smaller free energy span in the Ir catalytic cycle compared to an analogous Rh cycle accounts for this difference in activity. Moreover, both migratory insertion and reductive elimination were more facile in the Ir-

Theresa Sperger grew up in Austria and received her M.Sc. degree in Chemistry from ETH Zurich in 2014. She joined the Schoenebeck AL


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group for her M.Sc. thesis before starting her doctoral studies in 2014 as an Evonik Foundation scholar. Her doctoral research is focused on combined experimental and computational studies of dinuclear Pd(I) and Pd(III) complexes and their reactivities.

Franziska Schoenebeck was born and raised in Berlin, Germany. From 2001 to 2004, she studied Chemistry at the Technical University of Berlin and the University of Strathclyde in Glasgow, U.K. She undertook her Ph.D. studies in experimental organic chemistry in the group of Prof. John A. Murphy at the WestCHEM Research School in Glasgow, U.K. In 2008 she moved to California to work with Prof. K. N. Houk at UCLA, where she was involved in computational studies of organic reactivity. In 2010, Franziska joined the faculty of the ETH Zürich as Assistant Professor. Since 2013, she has been Professor at the RWTH Aachen University.

ACKNOWLEDGMENTS We thank the RWTH Aachen University, the MIWF NRW, the Evonik Foundation (scholarship to T.S.), and ETH Zurich (studentship to I.A.S.) for financial support. We appreciate the generous help of Henry C. Fisher with manuscript editing and helpful suggestions. REFERENCES Italo A. Sanhueza was born in Chile but raised in Sweden. He received his M.Sc. degree in Chemical Engineering from Uppsala University in 2011. Subsequently, he joined the Schoenebeck group for his Ph.D. studies. His doctoral research involves understanding organic and organometallic reactivity using a combined computational and experimental approach.

(1) Sameera, W. M. C.; Maseras, F. Transition Metal Catalysis by Density Functional Theory and Density Functional Theory/Molecular Mechanics. WIREs Comput. Mol. Sci. 2012, 2, 375−385. (2) Tsang, A. S. K.; Sanhueza, I. A.; Schoenebeck, F. Combining Experimental and Computational Studies to Understand and Predict Reactivities of Relevance to Homogeneous Catalysis. Chem.Eur. J. 2014, 20, 16432−16441. (3) Jackson, K.; Jaffar, S. K.; Paton, R. S. Computational Organic Chemistry. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2013, 109, 235− 255. (4) Schwerdtfeger, P. The Pseudopotential Approximation in Electronic Structure Theory. ChemPhysChem 2011, 12, 3143−3155. (5) Dolg, M.; Cao, X. Relativistic Pseudopotentials: Their Development and Scope of Applications. Chem. Rev. 2011, 112, 403−480. (6) Soriano, E.; Fernandez, I. Allenes and Computational Chemistry: From Bonding Situations to Reaction Mechanisms. Chem. Soc. Rev. 2014, 43, 3041−3105. (7) Geerlings, P.; Ayers, P. W.; Toro-Labbé, A.; Chattaraj, P. K.; De Proft, F. The Woodward−Hoffmann Rules Reinterpreted by Conceptual Density Functional Theory. Acc. Chem. Res. 2012, 45, 683−695. (8) Haller, L. J. L.; Macgregor, S. A.; Panetier, J. A. Computational Studies on the Reactivity of Transition Metal Complexes Featuring NHeterocyclic Carbene Ligands. N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools; The Royal Society of Chemistry: Cambridge, UK, 2011; pp 42−76. (9) Clot, E.; Norrby, P.-O. Modeling in Homogeneous Catalysis: A Tutorial. Innovative Catalysis in Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2012; pp 167−191. (10) Sakaki, S.; Ohnishi, Y.-Y.; Sato, H. Theoretical and Computational Studies of Organometallic Reactions: Successful or Not? Chem. Rec. 2010, 10, 29−45. (11) Fan, T.; Lin, Z. Theoretical Insights into Transition MetalCatalyzed Reactions of Carbon Dioxide. Understanding Organometallic Reaction Mechanisms and Catalysis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2014; pp 121−144. (12) Kretschmer, R.; Schlangen, M.; Schwarz, H. Mechanisms of Metal-Mediated C−N Coupling Processes: A Synergistic Relationship between Gas-Phase Experiments and Computational Chemistry. Understanding Organometallic Reaction Mechanisms and Catalysis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2014; pp 1−16. (13) Polynski, M. V.; Ananikov, V. P. Computational Modeling of Graphene Systems Containing Transition Metal Atoms and Clusters. Understanding Organometallic Reaction Mechanisms and Catalysis; WileyVCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2014; pp 321− 374. (14) Schoenebeck, F. Ligand, Additive, and Solvent Effects in Palladium Catalysis−Mechanistic Studies En Route to Catalyst Design.

Indrek Kalvet is from Estonia and obtained his M.Sc. degree (cum laude) in Chemistry from the University of Tartu. He has also gained additional experience by conducting research at the Queen’s University (Canada) and working at TBD Biodiscovery (Estonia). Indrek joined the Schoenebeck group in 2013 for his doctoral studies, focusing on combined computational and experimental mechanistic studies of Pdand Ni-catalyzed reactions.

AM


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O,O)2Ir(X) Complexes (X = CH3COO, OH). Organometallics 2008, 27, 6440−6445. (526) Lara, P.; Paneque, M.; Poveda, M. L.; Santos, L. L.; Valpuesta, J. E. V.; Carmona, E.; Moncho, S.; Ujaque, G.; Lledós, A.; Á lvarez, E.; Mereiter, K. Experimental and Computational Studies on the Iridium Activation of Aliphatic and Aromatic C−H Bonds of Alkyl Aryl Ethers and Related Molecules. Chem.Eur. J. 2009, 15, 9034−9045. (527) Lara, P.; Paneque, M.; Poveda, M. L.; Santos, L. L.; Valpuesta, J. E. V.; Salazar, V.; Carmona, E.; Moncho, S.; Ujaque, G.; Lledós, A.; Maya, C.; Mereiter, K. Synthetic, Mechanistic, and Theoretical Studies on the Generation of Iridium Hydride Alkylidene and Iridium Hydride Alkene Isomers. Chem.Eur. J. 2009, 15, 9046−9057. (528) Zhou, M.; Balcells, D.; Parent, A. R.; Crabtree, R. H.; Eisenstein, O. Cp* Iridium Precatalysts for Selective C−H Oxidation via Direct Oxygen Insertion: A Joint Experimental/Computational Study. ACS Catal. 2011, 2, 208−218. (529) García-Melchor, M.; Gorelsky, S. I.; Woo, T. K. Mechanistic Analysis of Iridium(III) Catalyzed Direct C−H Arylations: A DFT Study. Chem.Eur. J. 2011, 17, 13847−13853. (530) Join, B.; Yamamoto, T.; Itami, K. Iridium Catalysis for C−H Bond Arylation of Heteroarenes with Iodoarenes. Angew. Chem., Int. Ed. 2009, 48, 3644−3647. (531) Pahls, D. R.; Allen, K. E.; Goldberg, K. I.; Cundari, T. R. Understanding the Effect of Ancillary Ligands on Concerted Metalation−Deprotonation by (dmPhebox)Ir(OAc)2(H2O) Complexes: A DFT Study. Organometallics 2014, 33, 6413−6419. (532) For a related computational study on the role of the chelating base in Ir-catalyzed C−H activation, see: Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-Bahamonde, A. I. Computational and synthetic studies on the cyclometallation reaction of dimethylbenzylamine with [IrCl2Cp*]2: role of the chelating base. Dalton Trans. 2009, 5887−5893. (533) Rahaman, S. M. W.; Dinda, S.; Sinha, A.; Bera, J. K. A Noninnocent Cyclooctadiene (COD) in the Reaction of an “Ir(COD)(OAc)” Precursor with Imidazolium Salts. Organometallics 2012, 32, 192−201. (534) Meredith, J. M.; Robinson, R.; Goldberg, K. I.; Kaminsky, W.; Heinekey, D. M. C−H Bond Activation by Cationic Iridium(III) NHC Complexes: A Combined Experimental and Computational Study. Organometallics 2012, 31, 1879−1887. (535) Rahaman, S. M. W.; Dinda, S.; Ghatak, T.; Bera, J. K. Carbon Monoxide Induced Double Cyclometalation at the Iridium Center. Organometallics 2012, 31, 5533−5540. (536) Laviska, D. A.; Guan, C.; Emge, T. J.; Wilklow-Marnell, M.; Brennessel, W. W.; Jones, W. D.; Krogh-Jespersen, K.; Goldman, A. S. Addition of C−C and C−H Bonds by Pincer-Iridium Complexes: A Combined Experimental and Computational Study. Dalton Trans. 2014, 43, 16354−16365. (537) Wu, H.; Hall, M. B. Carbon-Hydrogen vs. Carbon-Halogen Oxidative Addition of Chlorobenzene by a Neutral Iridium Complex Explored by DFT. Dalton Trans. 2009, 30, 5933−5942. (538) Biswas, S.; Huang, Z.; Choliy, Y.; Wang, D. Y.; Brookhart, M.; Krogh-Jespersen, K.; Goldman, A. S. Olefin Isomerization by Iridium Pincer Catalysts. Experimental Evidence for an η3-Allyl Pathway and an Unconventional Mechanism Predicted by DFT Calculations. J. Am. Chem. Soc. 2012, 134, 13276−13295. (539) Liu, F.; Pak, E. B.; Singh, B.; Jensen, C. M.; Goldman, A. S. Dehydrogenation of n-Alkanes Catalyzed by Iridium “Pincer” Complexes: Regioselective Formation of α-Olefins. J. Am. Chem. Soc. 1999, 121, 4086−4087. (540) Hackenberg, J. D.; Kundu, S.; Emge, T. J.; Krogh-Jespersen, K.; Goldman, A. S. Acid-Catalyzed Oxidative Addition of a C−H Bond to a Square Planar d8 Iridium Complex. J. Am. Chem. Soc. 2014, 136, 8891− 8894. (541) Schwartsburd, L.; Iron, M. A.; Konstantinovski, L.; DiskinPosner, Y.; Leitus, G.; Shimon, L. J. W.; Milstein, D. Synthesis and Reactivity of an Iridium(I) Acetonyl PNP Complex. Experimental and Computational Study of Metal−Ligand Cooperation in H−H and C−H

Bond Activation via Reversible Ligand Dearomatization. Organometallics 2010, 29, 3817−3827. (542) For further theoretical studies involving pincer complexes, see: Feng, Y.; Wang, C.; Fan, H. Theoretical Studies on the Intra- and Intermolecular C−H Activation by T-Shaped Pincer Complexes. J. Organomet. Chem. 2011, 696, 4064−4069. (543) Frasco, D. A.; Lilly, C. P.; Boyle, P. D.; Ison, E. A. Cp*Ir(III)Catalyzed Oxidative Coupling of Benzoic Acids with Alkynes. ACS Catal. 2013, 3, 2421−2429. (544) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Versatile Synthesis of Isocoumarins and α-Pyrones by Ruthenium-Catalyzed Oxidative C−H/O−H Bond Cleavages. Org. Lett. 2012, 14, 930−933. (545) Li, J.; Hu, W.; Peng, Y.; Zhang, Y.; Li, J.; Zheng, W. Theoretical Study on Iridacycle and Rhodacycle Formation via C−H Activation of Phenyl Imines. Organometallics 2014, 33, 2150−2159. (546) For a related acetate-assisted transformation, see: Carr, K. J. T.; Davies, D. L.; Macgregor, S. A.; Singh, K.; Villa-Marcos, B. Metal control of selectivity in acetate-assisted C−H bond activation: an experimental and computational study of heterocyclic, vinylic and phenylic C(sp2)−H bonds at Ir and Rh. Chem. Sci. 2014, 5, 2340−2346. (547) Meier, S. K.; Young, K. J. H.; Ess, D. H.; Tenn, W. J.; Oxgaard, J.; Goddard, W. A., III; Periana, R. A. Heterolytic Benzene C−H Activation by a Cyclometalated Iridium(III) Dihydroxo Pyridyl Complex: Synthesis, Hydrogen−Deuterium Exchange, and Density Functional Study. Organometallics 2009, 28, 5293−5304. (548) Rhinehart, J. L.; Manbeck, K. A.; Buzak, S. K.; Lippa, G. M.; Brennessel, W. W.; Goldberg, K. I.; Jones, W. D. Catalytic Arene H/D Exchange with Novel Rhodium and Iridium Complexes. Organometallics 2012, 31, 1943−1952. (549) For a similar catalytic system employing a Rh(I)−diimide catalyst, see: Webster-Gardiner, M. S.; Fu, R.; Fortman, G. C.; Nielsen, R. J.; Gunnoe, T. B.; Goddard, W. A., III Arene C−H Activation Using Rh(I) Catalysts Supported by Bidentate Nitrogen Chelates. Catal. Sci. Technol. 2015, 5, 96−100. (550) Perutz, R. N.; Braun, T. 1.26-Transition Metal-mediated C−F Bond Activation. In Comprehensive Organometallic Chemistry III; Crabtree, D. M. P. M. H., Ed.; Elsevier: Oxford, 2007; Vol. 1, pp 725−758. (551) Erhardt, S.; Macgregor, S. A. Computational Study of the Reaction of C6F6 with [IrMe(PEt3)3]: Identification of a PhosphineAssisted C−F Activation Pathway via a Metallophosphorane Intermediate. J. Am. Chem. Soc. 2008, 130, 15490−15498. (552) Choi, J.; Wang, D. Y.; Kundu, S.; Choliy, Y.; Emge, T. J.; KroghJespersen, K.; Goldman, A. S. Net Oxidative Addition of C(sp3)−F Bonds to Iridium via Initial C−H Bond Activation. Science 2011, 332, 1545−1548. (553) Kundu, S.; Choi, J.; Wang, D. Y.; Choliy, Y.; Emge, T. J.; KroghJespersen, K.; Goldman, A. S. Cleavage of Ether, Ester, and Tosylate C(sp3)−O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C−H Bonds. Experimental and Computational Studies. J. Am. Chem. Soc. 2013, 135, 5127−5143. (554) Haibach, M. C.; Lease, N.; Goldman, A. S. Catalytic Cleavage of Ether C−O Bonds by Pincer Iridium Complexes. Angew. Chem., Int. Ed. 2014, 53, 10160−10163. (555) Haibach, M. C.; Guan, C.; Wang, D. Y.; Li, B.; Lease, N.; Steffens, A. M.; Krogh-Jespersen, K.; Goldman, A. S. Olefin Hydroaryloxylation Catalyzed by Pincer−Iridium Complexes. J. Am. Chem. Soc. 2013, 135, 15062−15070. (556) Dang, T. T.; Boeck, F.; Hintermann, L. Hidden Brønsted Acid Catalysis: Pathways of Accidental or Deliberate Generation of Triflic Acid from Metal Triflates. J. Org. Chem. 2011, 76, 9353−9361. (557) Yamamoto, H.; Futatsugi, K. “Designer Acids”: Combined Acid Catalysis for Asymmetric Synthesis. Angew. Chem., Int. Ed. 2005, 44, 1924−1942. (558) Sevov, C. S.; Hartwig, J. F. Iridium-Catalyzed, Intermolecular Hydroetherification of Unactivated Aliphatic Alkenes with Phenols. J. Am. Chem. Soc. 2013, 135, 9303−9306. BB


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