Computation and Experiment: A Powerful Combination to Understand

Article pubs.acs.org/accounts

Computation and Experiment: A Powerful Combination to Understand and Predict Reactivities Published as part of the Accounts of Chemical Research special issue “Computational Catalysis for Organic Synthesis”. Theresa Sperger,† Italo A. Sanhueza,†,‡ and Franziska Schoenebeck*,† †

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

‡

CONSPECTUS: Computational chemistry has become an established tool for the study of the origins of chemical phenomena and examination of molecular properties. Because of major advances in theory, hardware and software, calculations of molecular processes can nowadays be done with reasonable accuracy on a time-scale that is competitive or even faster than experiments. This overview will highlight broad applications of computational chemistry in the study of organic and organometallic reactivities, including catalytic (NHC-, Cu-, Pd-, Ni-catalyzed) and noncatalytic examples of relevance to organic synthesis. The selected examples showcase the ability of computational chemistry to rationalize and also predict reactivities of broad significance. A particular emphasis is placed on the synergistic interplay of computations and experiments. It is discussed how this approach allows one to (i) gain greater insight than the isolated techniques, (ii) inspire novel chemistry avenues, and (iii) assist in reaction development. Examples of successful rationalizations of reactivities are discussed, including the elucidation of mechanistic features (radical versus polar) and origins of stereoselectivity in NHC-catalyzed reactions as well as the rationalization of ligand effects on ligation states and selectivity in Pd- and Ni-catalyzed transformations. Beyond explaining, the synergistic interplay of computation and experiments is then discussed, showcasing the identification of the likely catalytically active species as a function of ligand, additive, and solvent in Pd-catalyzed cross-coupling reactions. These may vary between mono- or bisphosphine-bound or even anionic Pd complexes in polar media in the presence of coordinating additives. These fundamental studies also inspired avenues in catalysis via dinuclear Pd(I) cycles. Detailed mechanistic studies supporting the direct reactivity of Pd(I)−Pd(I) with aryl halides as well as applications of air-stable dinuclear Pd(I) catalysts are discussed. Additional combined experimental and computational studies are described for alternative metals, these include the discussion of the factors that control C−H versus C−C activation in the aerobic Cu-catalyzed oxidation of ketones, and ligand and additive effects on the nature and favored oxidation state of the active catalyst in Ni-catalyzed trifluoromethylthiolations of aryl chlorides. Examples of successful computational reactivity predictions along with experimental verifications are then presented. This includes the design of a fluorinated ligand [(CF3)2P(CH2)2P(CF3)2] for the challenging reductive elimination of ArCF3 from Pd(II) as well as the guidance of substrate scope (functional group tolerance and suitable leaving group) in the Ni-catalyzed trifluoromethylthiolation of C(sp2)−O bonds. In summary, this account aims to convey the benefits of integrating computational studies in experimental research to increase understanding of observed phenomena and guide future experiments.

1. INTRODUCTION

as “physical organic chemistry”, has specialized in utilizing

The continuous search for the origins of chemical phenomena has stimulated generations of organic chemists to make use of physical tools to gain insight on structure, properties and reactivity relationships. This subdiscipline, commonly referred to

analytical tools as well as developing approaches (e.g., Hammett

© XXXX American Chemical Society

Received: February 8, 2016

A

DOI: 10.1021/acs.accounts.6b00068 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

of chiral organic cyclo-adducts,8 reactivity and selectivity aspects of novel amide bond formation,9,10 the origins of selectivity in natural product synthesis,11 and property calculations in a medicinal chemistry context.12 Many of these investigations were undertaken in collaboration with researchers from academia and industry. An example is our study of the enantiomerization mechanism of strained cyclic buta-1,3-dienes, in collaboration with Diederich and co-workers.8 This project aimed to prepare optically active compounds that may be utilized as chiral memory units or chiral sensors. However, key to application is that the molecule remains chiral. Thus, an understanding (as well as quantification) of the enantiomerization mechanism could aid the development of appropriate molecules. While chemical intuition might suggest that chair-conformers are adopted along the pathway, it was computationally found that the energetically most feasible route involves an initial flip from the chairlike geometry to the energetically higher boat-conformer, followed by isomerization. Notably, the predicted activation barrier for the process was in excellent agreement with experimental measurements (Scheme 1a).

plots, kinetic analyses, isotope effects...) to identify mechanistic details and/or gain indirect information on the nature of transition states. A more recent addition to the plethora of tools is computational chemistry. Owing to the tremendous progress in the development of hardware, software, and theoretical methods, computational chemistry has evolved to a powerful tool that allows one to gain mechanistic information and study the nature of transition states directly, allowing therefore the analysis of the origins of selectivity or the study of more complex reactivity scenarios, such as those related to catalysis as well as property prediction. There are numerous computational tools available, each of which has its own strengths and weaknesses, as well as applications for which it has been developed.1 In reactivity studies of small organic and organometallic molecules (∼60 atoms, excluding hydrogen), quantum mechanical approaches of good accuracy are nowadays fast enough to be competitive with experiments. To give an illustration of the tremendous progress in possibilities: if we wanted to study the bond making and breaking of a Diels−Alder reaction, one would typically optimize the transition state (TS) in a static fashion employing quantum mechanics. While calculation times of about 6 months were necessary in the 1980s,2 using Hartree−Fock (HF) theory and a small basis set on a supercomputer of that time, nowadays, the exact same calculation can be done in roughly 15 s.3 For comparison, a standard DFT approach takes 258 s for the same TS optimization.4 Since calculations are nowadays this fast, sometimes even faster than experiments, it is reasonable to question why calculations are not universally applied, instead of doing experiments. This is on the one hand ascribable to the accuracy (or lack thereof) of the theoretical method employed, but also the fact that the interesting reactivity problems tend to be more complex, larger in size and with many more mechanistic possibilities. Consequently, the time it takes to gain unambiguous mechanistic information is also increased. However, when teamed with experiments, computations can be very valuable, and the synergistic approach of computation and experiment will arguably gain more insight than any of the isolated techniques. In this account we describe our activities in using computational chemistry to (i) understand organic and organometallic transformations as well as (ii) guide our experiments in the development of novel chemistry. In this context, we will showcase the predictive capability of computational chemistry and will emphasize the synergistic power of combining calculations with experiments.

Scheme 1. (a) Enantiomerization of Cyclic Buta-1,3-dienes via boat-TS and (b) Ring Contraction of Spirocyclopropane Isoxazolidines

a

Energies (in kcal/mol).

Challenging synthetic problems have always stimulated mechanistic investigations and reaction development. The Carreira group developed an elegant total synthesis of gelsemoxonine, involving a ring contraction of a spirocyclopropane isoxazolidine as the key step.11 Experimental mechanistic probes revealed that the process is highly stereoretentive, indicating that the mechanism is either concerted or proceeds via intermediates that cannot undergo rotation. Computations revealed that initial N-protonation of the isoxazolidine is crucial to trigger the ring contraction (lowering the barrier by 20 kcal/ mol relative to the nonprotonated pathway). The ethylene extrusion was found to be concerted and no intermediate was formed along the reaction coordinate, converting directly into the products. While the N−O cleavage transition state was found to have some biradical character (revealed through (U)CCSD(T), CASSCF, and RO−DFT methodology), there is a transition to a polar mechanism along the reaction coordinate (Scheme 1b).

2. STUDYING ORGANIC (NONCATALYTIC) TRANSFORMATIONS Several decades of excellent physical organic chemistry research provided chemists with an intuitive reactivity understanding of potential and reasonable mechanistic scenarios for many organic transformations.5 However, to be able to explain certain selectivities or slight variations in electronic properties (e.g., polar versus radical mechanisms), experimental mechanistic approaches have been limited to provide thorough understanding, since the nature of the transition state is the key controlling factor. It is in these cases where computations have provided valuable insight. Over the past years, our research group has studied organic reactivity aspects in relation to functional organic molecules and synthesis. These include the mechanistic details of rearrangements of push−pull chromophores6 (including those connected to fullerenes7), enantiomerization processes

3. STUDYING ORGANOMETALLIC TRANSFORMATIONS Metals (whether heterogeneous, homogeneous, or within an enzyme pocket) may induce reactivities that cannot be achieved B


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Table 1. Commonly-Employed DFT Methods in the Schoenebeck Group to Study Organic and Organometallic Reactivities geometry optimization energy calculation (single point energy correction)

organic

organometallic

B3LYP B3LYP, M06-2X

B3LYP, B3LYP-D3, ωB97XD M06L, M06, B3LYP-D3, PBE0-D3, ωB97XD

Scheme 2. Dispersion Allows Location of Bisligated Oxidative Addition TS of Aryl Triflate

form a monoligated Pd(0) species. This implies that no “Pd(0)L” is ever “free” in solution but rather a species that is bound to a substrate or solvent.18,19

through purely organic reactivity modes. Organometallic chemistry has therefore been coined as a field that likely provides future innovative synthetic transformations.13 Given the unique reactivities, organometallic transformations are currently less intuitive, making it often challenging to predict the reaction outcome a priori. Consequently, the choice of ideal additive, solvent, and metal for the desired reactivity and selectivity is frequently a result of experimental screening and/or serendipity. This is particularly the case for catalysis-related research. To guide research toward innovative solutions, greater understanding of the underlying processes will be valuable. Using a synergistic approach of computation and experiment, our group succeeded in gaining greater understanding but also in guiding novel experiments. In terms of applicable computational methodology, our group recently undertook a statistical analysis of commonly employed DFT methods in the study of organometallic transformations (involving Pd, Ni, Rh, and Ir). This analysis showed that the B3LYP method is rather popular in calculations involving transition metals, in particular for the optimization of structures.14 However, for energy calculations, we and others generally employ methods that better account for dispersion since many organometallic transformations involve significant intramolecular dispersive interactions. Table 1 summarizes DFT-methods most frequently employed in our group for the study of organic and organometallic investigations. While many similarities exist between our organic and organometallic computational approaches, we preferred the MO6Lmethod in the computational evaluation of organometallic systems.15,16 Although B3LYP can give excellent results and be sufficient in geometry optimizations, if dispersion is not crucial, questions addressing nuclearity or ligation state will require the consideration of dispersion. An example from our lab is the search for bisligated transition states for the oxidative addition of aryl triflates to Pd(PtBu3)2.17 While methods that do not account well for dispersion, such as B3LYP or PBE0, resulted in ligand dissociation, the inclusion of dispersion (ωB97XD or B3LYP-D3 methodology) allowed for the first location of a bisligated oxidative addition transition state with Pd(PtBu3)2 (Scheme 2). Importantly, for bulky phosphine ligands, such as PtBu3, it is commonly assumed that a monoligated “Pd(0)L” species would be reactive, on the basis of the previous computational inability to locate bisphosphine transition states as well as experimental kinetic data. The inclusion of dispersion in calculations suggested an associative mechanism with a substrate to be preferred over the previously proposed dissociation of one phosphine ligand to

4. MECHANISTIC STUDIES OF TRANSFORMATIONS RELATED TO CATALYSIS 4.1. General Remarks

Catalysis is highly important and arguably a key discipline where chemists might make a contribution to finding solutions to global challenges and creating a more sustainable life. It also revolutionized the way chemists assemble molecules and has consequently been recognized with several Nobel prizes. The computational study of catalytic transformations differs from its corresponding noncatalytic counterpart in several aspects:20 (i) there are frequently various intermediates and steps to consider within a complex catalytic cycle, which may in turn depend on additives and conditions employed; (ii) several competing pathways need to be evaluated, discriminated only by very small energetic differences; and (iii) there is a need to address several conformers that arise from flexible catalysts and/ or ligands. An exemplification of the aforementioned challenges is our study on the origins of stereoselectivity of an NHC-catalyzed annulation reaction, developed by Bode and co-workers.21 While a Claisen rearrangement was identified as the stereodetermining step, the favored protonation states (i.e., enol or enolate) of the transition state and intermediates were unknown. We investigated the factors that control stereoselectivity and found that the protonated transition states for the two competing stereochemical outcomes gave no stereoselectivity. Moreover, the consideration of various potentially reactive conformers in the context of a Boltzman-weighted average of the transition state (TS) ensembles showed that presence of a proton would diminish selectivity. Only a deprotonated pathway would result in discrimination of stereoisomers, consistent with electrostatic repulsion of the formed enolate with the π-system of the phenylsubstituted acyl azolium-catalyst in the disfavored transition state (Scheme 3). Notably, while different mechanisms were assumed (Claisen rearrangement versus Michael addition), the computed transition states are in this case structurally identical for both Claisen rearrangement and conjugate addition. A similar mechanistic analysis was conducted in collaboration with the Enders group. In this study, also multiple mechanistic scenarios were considered, such as anionic, neutral, and radical pathways in addition to exo and endo selectivity modes of ring C


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ing, since the precise mechanisms and structural features of key catalytic species are unknown. In this regard, we set out to investigate the influences of catalyst, substrate, solvent, and base on the selectivity of Cu-catalyzed aerobic oxidations of ketones (Scheme 4).25 Key experiments were conducted that revealed

Scheme 3. Enantioselective NHC-Catalyzed Annulation via Deprotonated Pathway

Scheme 4. Mechanistic Divergence in Cu-Catalyzed Aerobic Oxidation Resulting from an α-Peroxo Ketone As a Common Intermediate

closures in the sequential organo- and Ag-catalyzed synthesis of spiropyrazolones.22 Our calculations at the CPCM (DCM) M06/def2-TZVP//B3LYP/6-31G(d) level of theory suggested that a neutral pathway possesses prohibitively high activation barriers, and that instead an anionic pathway is adopted favoring the 5-exo-dig cyclization. The role of Ag is to overcome the endergonicity of this step, rendering the cyclization thermodynamically favored. Notably, depending on the substrate, there may be a divergence in mechanism. An alternative Ag-free process was experimentally found to only occur in the presence of oxygen and could computationally be attributed to an oxidation-induced radical pathway. This alternative pathway was favored only for a phenyl-substituted substrate and significantly less for other substrates explaining their lack of reactivity under Ag-free conditions. These examples illustrate that the number of possibilities to explore in the context of catalysis is tremendously increased. This inherent complexity of the chemical system is a reason as to why transformations are not uniformly calculated, instead of doing experiments. However, the study of specific mechanistic questions of single steps, particularly in a qualitative manner, i.e., when comparing two systems relative to each other and when teamed up with experiments is likely much more powerful and even predictive, as we will discuss below.

that the selectivity of oxidation likely arises from a common intermediate, i.e., an α-peroxo ketone. While both C−C bond cleavage and C−H functionalization were computationally found to be consistent with a radical mechanism, the precise formation of alcohol from the peroxide intermediate remained unknown. Thus, we synthesized the putative peroxide intermediate and experimentally uncovered a novel base-triggered reduction mechanism. Similarly, combining calculations with experiments aided our mechanistic study on the exclusively trans-selective chlorocarbamoylation of alkynes.26 In collaboration with the Lautens group, we investigated two plausible mechanistic pathways that can account for the exclusive formation of trans-product (Scheme 5). An ionic trans-chloropalladation pathway could be ruled out experimentally, since no halide exchange was observed upon

4.2. Combined Experimental and Computational Approach to Gain Mechanistic Information on Reactivity- and Selectivity-Controlling Factors in Catalysis

Scheme 5. Proposed Mechanistic Pathways of the transSelective Chlorocarbamoylation of Alkynes

We have studied the effects of ligand, additive, and solvent to gain insights on active catalytic species, potential mechanistic pathways, and key controlling factors.14,20,23 In this context, the use of a combined computational and experimental approach has proven highly beneficial: on the one hand, computations allow the study of key intermediates and also transition states, which are challenging to monitor via conventional experimental approaches. On the other hand, experiments give valuable insight on computationally challenging scenarios (such as ionic pathways, small energetic differences, method dependences)24 and can therefore be used to validate computational results or assist computations. While this synergistic approach is, in principle, applicable to a variety of metal-containing and metalfree reactivities, we will showcase selected examples of our own work in relation to Cu-, Pd-, and Ni-catalysis. There has been significant interest in aerobic homogeneous catalysis with nonprecious metals, but one of the key challenges is its selectivity and control thereof. Additionally, the understanding of underlying selectivity-controlling factors is challengD


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with dppf (1,1′-bis(diphenylphosphino)ferrocene) and Cl. In addition, computations and experiments helped to understand the effect of ligand. Experiments revealed the favored catalyst resting state as (L)Ni(cod) for L=dppf and Ni(L)2 for L=dppe. The labile cod ligand in the resting state was computationally revealed to be a key for efficient catalysis as it readily dissociates prior to oxidative addition. By contrast, Ni(dppe)2 suffers from a large ligand dissociation energy, which renders the system unreactive under the mild reaction conditions employed. Moreover, MeCN was identified as an efficient traceless additive, resulting in a widely applicable protocol for the trifluoromethylthiolation of a variety of substrates and biologically relevant molecules. The question of the truly catalytically active species is a classic problem in catalysis, especially when several ligation states need to be considered. Another dimension of complexity arises when charged species may also be involved. Here, preferences of adduct formation cannot readily be determined, as different charge states are involved. In this context, an enduring question was the potential involvement of anionic Pd as catalytically active species.28,29 While charged species were previously experimentally detected through electrochemical studies, it was uncertain whether they could also be reactive.30 We addressed this question with a selectivity probe and deduced mechanistic information indirectly through a combined experimental/computational approach. We studied the chemoselectivity of Suzuki-Miyaura cross-coupling of 4-chlorophenyl triflate and experimentally discovered that a switch in solvent from THF to a more polar solvent, such as DMF, results in reversal of selectivity from C−Cl to C−OTf functionalization.31,32 A qualitative comparison of experiments with computations suggested that the observed selectivity switch is inconsistent with the reactivity of a monoligated Pd(PtBu3) catalyst, which has generally been proposed as the catalytically active species for this catalyst system.33 Instead, calculations are in line with the reactivity of an anionic Pd catalyst, which forms in the presence of coordinating species. Control experiments of the computationally derived conclusions in the absence of coordinating additives (e.g., KF) and by employing noncoordinating stannane transmetallating agents instead of boronic acids led to C−Cl addition even in polar solvent (Scheme 7, left). Addition of KF, on the other hand, reversed the selectivity again to C−OTf addition.

addition of an exogeneous halide. An alternative pathway involving cis-carbopalladation and fast subsequent cis-trans isomerization was further studied by means of calculations at the CPCM (toluene) M06L/def2-TZVP//B3LYP/6-31G(d) (LANL2DZ) level of theory. Calculations indicated that both ciscarbopalladation as well as cis-trans isomerization proceed with feasible energetic barriers of 14.7 and 2.4 kcal/mol, respectively. The low barrier for isomerization is significantly favored over direct reductive elimination of cis-product, thus leading to the sole formation of trans-product as the kinetically and thermodynamically favored product. We have also applied computational investigations in the development of a Ni-catalyzed protocol for the trifluoromethylthiolation of aryl and heteroaryl chlorides (see Scheme 6).27 Scheme 6. Ni(0)/Ni(II)-Catalyzed Trifluoromethylthiolation of Aryl Chlorides

In this study, computations rationalized and aided the development of the first efficient C-SCF3 functionalization of aryl chlorides using Ni-catalysis. Our results suggest that the reactivity is in line with a Ni(0)/Ni(II) pathway, since the specifically prepared Ni(II)(Ar)(Cl) was shown to be a competent precatalyst and intermediate. An alternative mechanism involving Ni(I) as a reactive species could be ruled out, as this species proved to be catalytically incompetent. Notably, in this context we isolated and characterized a rare Ni(I)-monomer

Scheme 7. Using 4-Chlorophenyl Triflate As a Selectivity Probe and the Experimental Parameters That We Identified to Switch Selectivity

E


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Accounts of Chemical Research Scheme 8. Reactivity of Halide-Bridged Pd(I) Dimers: Pd(0)- (Red) versus Pd(I)-Catalysis (Green)

B3LYP/6-31+G(d) (SDD) level of theory indicated that a direct disproportionation is unlikely. Instead the Pd(I) dimer activation is induced by a nucleophile.36 Thus, under additive-free conditions, the Pd(I) dimer should remain stable and we therefore next investigated the fundamental question whether a Pd(I) dimer could react directly as a catalyst. Subjecting the bromide-bridged Pd(I) dimer to an aryl iodide, we observed formation of the corresponding aryl bromide. This indicated that a halide exchange had taken place and was the first positive indication that Pd(I) dimers might directly react with aryl halides.37 We employed a combination of experimental and computational tools to investigate whether the Pd(I) dimer was indeed directly involved in this halide-exchange process and to rule out alternative mechanisms. Our investigations showed that a Pd(0)/Pd(II) mechanism was unlikely. Pd(II) intermediates could not be observed during the stoichiometric reaction and when independently synthesized were not yielding the product under the analogous reaction conditions. Also, an alternative Pd(I) radical mechanism was shown to be rather unlikely, since our experimental studies generating Pd(I) radicals via known methods only resulted in trace amounts of aryl bromide product. In addition, the presence of radical trapping agents did not significantly affect the reaction outcome. This was further supported by calculations at the CPCM (THF) M06L/6-311+ +G(d,p) (SDD)//B3LYP/6-31G(d) (SDD) level of theory which indicate that the radical mechanism is energetically disfavored over the dinuclear pathway. Instead, the data suggest that the halide-exchange process is likely to be thermodynamically driven and can occur via a direct oxidative addition to the Pd(I)−Pd(I) framework. Furthermore, kinetic measurements support this mechanism by showing that the reaction follows a first-order dependence in both aryl iodide and Pd(I) dimer.38 The dinuclear reactivity of Pd(I) not only represents an alternative to the textbook Pd(0)/Pd(II) mechanism but also a concept in catalysis that may have significant potential in methodology development. First, we identified that the more robust iodide-bridged Pd(I) dimer is completely bench-stable, while Pd(0) catalysts are typically not. Thus, we subsequently investigated the potential of dinculear Pd(I) catalysis for new types of cross-coupling reactions such as the formation of C− SCF339 and C−SeCF340 bonds. The prerequisites for the successful application of the concept of dinuclear Pd(I) reactivity of are 2-fold: (i) the employed nucleophile needs to be able to replace the bridging moieties of the dinuclear Pd(I) catalyst, and (ii) the nucleophile needs to be able to act as a bridging moiety itself in order to preserve the dinuclear Pd(I) framework. Applying these guidelines, we were able to develop catalytic protocols for the formation of C−SCF3 and C−SeCF3 bonds from aryl iodides and bromides.39,40 DFT-calculations and NMR monitoring studies were in line with the direct reactivity of

Utilizing the same mechanistic probe and its inherent reactivity preference for addition of monoligated PdL at C−Cl and bisligated PdL2 at C−OTf, we also examined favored phosphine ligation states as a function of ligand and computational method. Implementation of dispersion in the calculation versus no-dispersion showed that the predicted site selectivity of mono- (C−Cl) versus bisphosphine (C−OTf) pathways differed by roughly 20 kcal/mol.17 While for PtBu3, C−Cl addition was calculated to be preferred (regardless whether dispersion was considered), our computations suggested that the essentially unexplored ligand, PiPrtBu2, could react via both mono- and bisphosphine transition states, thus possessing the ability to switch selectivity between C−Cl and C−OTf bond addition depending on the concentration of ligand utilized (Scheme 7, right).34 This suggests that dispersion is the selectivitycontrolling factor, indicating that it could become an additional guiding principle in the design of novel ligands. The synergy of computation and experiment was not only advantageous for the explanation of selectivity and elucidation of mechanistic pathways but also led us to the exploration of intriguing reactivities. In this context, we discovered that halidebridged Pd(I) dimers can form under reaction conditions usually encountered in Stille or Sonogashira cross-couplings. Our investigations showed that Cu- and Ag-additives typically employed in cross-coupling reactions lead to an oxidation of the Pd(0)(PtBu3)2 species. In this process, the corresponding halide-bridged Pd(I) dimer is formed under concomitant reduction of Cu- or Ag-salt. This observation is consistent with some of the contrasting observations of additive effects in cross coupling reactions. In the case of Suzuki-Miyaura crosscouplings, the effect of CuXn (X = Br, I; n = 1−2) salts depends on the employed anion. For X = Br, the bromide-bridged Pd(I) dimer is formed and readily liberates the catalytically active monophosphine Pd(0) species resulting in increased reaction rates. However, for X = I, an iodide-bridged Pd(I) dimer is formed, which is more robust than the corresponding bromo dimer and is less efficient in releasing Pd(0). Formation of this dimer will become severe for challenging cross-coupling, e.g., the Sonogashira reactions of aryl chlorides, since the formed Pd(I) dimer readily reacts with alkynes to initiate polymerization. We subsequently studied the reactivity of the dinuclear complexes in greater detail. Specifically, we wanted to understand whether the dimer will solely act as precatalyst for Pd(0) or whether it may also react directly. In this context, we studied catalysis derived from the bromide-bridged Pd(I) dimer [(PtBu3)PdBr]2 in order to obtain insights into the likely active catalytic species and applications in selective cross-coupling reactions (Scheme 8).35 By means of combining calculations with experiments we could show that the Pd(I) dimer reacts as a precatalyst for Pd(0)-based Suzuki cross-couplings. The calculations at the CPCM (THF) M06L/6-31+G(d) (SDD)// F


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Accounts of Chemical Research Scheme 9. Ligand Design to Facilitate Ar−CF3 Reductive Elimination from Pd(II)

suggested that although a range of C−OR moieties can in principle react with Ni, only the most reactive ones, triflates and nonaflates, are compatible with the reactivity window set by the C−SCF3 functionality. We verified these predictions experimentally and subsequently developed the first efficient method to functionalize C(sp2)−O bonds. Computations along with selected key mechanistic experiments served as a valuable tool to rapidly assess substrate scope while avoiding elaborate screening efforts. Importantly, the calculations were done on a competitive time scale (the complete TS-calculations took on average 11.5 h)50 to experiments, showing the potential of computationally assisted explorations of scope.

dinuclear Pd(I). In addition, we could show that the stable catalytic entity can be recovered after reaction completion. 4.3. Computational Prediction and Guide to Experimental Innovation

The design of chemical reactivity using computations as a predictive tool constitutes a long pursued goal of computational chemistry. However, examples in which computations have been implemented in the design of chemical reactivity are rather scarce or have not been tested experimentally.41−45 Therefore, we set out to investigate the challenging reductive elimination step in Ar−CF3 bond formation from Pd(II) complexes.46 This transformation has been proven difficult as only very few ligands have been reported to trigger the activation of the inert Pd−CF3 bond.47,48 By computationally comparing the experimentally efficient Xantphos ligand with smaller bite angle ligands, such as dppe, we uncovered that the latter can be rendered efficient for reductive elimination of Ar−CF3 if small and electrostatically repulsive ligand substituents are employed. By using this criterion as a guiding principle, we computationally designed a small bite angle ligand with CF3-subtituents and tested our computational design experimentally. After synthesizing the designed ligand and its corresponding ArPd(II)CF3 complex, efficient reductive elimination to yield PhCF3 was observed (Scheme 9). In contrast to steric effects, this study uses electrostatic repulsion as a design principle presenting potential for novel avenues in catalysis and new ideas for entirely novel ligand motifs and reactivities. While Ni has been shown to catalyze the functionalization of the least reactive aromatic C−OMe bonds49, unreactive C−C or C−H bonds were installed in those cases, excluding potential back-reactions of the formed products. Our group set the goal of developing the first Ni-catalyzed trifluoromethylthiolation of C(sp2)−O bonds. Our experiments showed, that the SCF3moiety of the product reacts with the Ni(0)-catalyst, causing its deactivation. Therefore, we computationally assessed the reaction scope and examined possible leaving groups, relative to the barrier of oxidative addition to Ar-SCF3 (Scheme 10). This

5. CONCLUSION We have showcased herein the power of the application of computational chemistry in the development and understanding of modern organic and organometallic chemistry. A particular emphasis was given to a combined computational and experimental approach, which allows for a greater and more unambiguous mechanistic insight than any of the isolated techniques may provide. Beyond rationalizing, we also showed examples of successful reactivity predictions, computational ligand designs and concepts to avoid a wasteful experimental screening through rapid computational assessment. We hope that this overview will further stimulate the synergistic use of calculations and experiment.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Theresa Sperger studied chemistry at ETH Zürich and received her M.Sc. in 2014. She subsequently joined the Schoenebeck group for her Ph.D. as an Evonik Foundation scholar. Her research interests involve the mechanistic study of catalytic reactions employing a combined experimental and computational approach.

Scheme 10. Assessment of Leaving Groups Compatible with Ni-Catalyzed Trifluoromethylthiolation

Italo A. Sanhueza received his M.Sc. degree in chemical engineering from Uppsala University in 2011. He is currently pursuing his Ph.D. in the Schoenebeck group focusing on the combined computational and experimental study of organic and organometallic reactivity. Franziska Schoenebeck studied chemistry at the TU Berlin and the University of Strathclyde in Glasgow. She received her Ph.D. from the WestCHEM Research School in Glasgow under the supervision of Prof. Murphy before joining Prof. Houk as a postdoctoral researcher in 2008 at UCLA. She started her independant research at the ETH Zürich in 2010. Since 2013, she has been professor at the RWTH Aachen University. G


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(20) 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. (21) Lyngvi, E.; Bode, J. W.; Schoenebeck, F. A computational study of the origin of stereoinduction in NHC-catalyzed annulation reactions of α,β-unsaturated acyl azoliums. Chem. Sci. 2012, 3, 2346−2350. (22) Hack, D.; Dürr, A. B.; Deckers, K.; Chauhan, P.; Seling, N.; Rübenach, L.; Mertens, L.; Raabe, G.; Schoenebeck, F.; Enders, D. Asymmetric Synthesis of Spiropyrazolones by Sequential Organo- and Silver Catalysis. Angew. Chem., Int. Ed. 2016, 55, 1797−1800. (23) Bonney, K. J.; Schoenebeck, F. Experiment and Computation: A Combined Approach to Study the Reactivity of Palladium Complexes in Oxidation States 0 to IV. Chem. Soc. Rev. 2014, 43, 6609−6638. (24) Sperger, T.; Fisher, H. C.; Schoenebeck, F. Computationally deciphering palladium-catalyzed reaction mechanisms. WIREs Comput. Mol. Sci. 2016, 6, 226. (25) Tsang, A. S. K.; Kapat, A.; Schoenebeck, F. Factors That Control C−C Cleavage versus C−H Bond Hydroxylation in Copper-Catalyzed Oxidations of Ketones with O2. J. Am. Chem. Soc. 2016, 138, 518−526. (26) Le, C. M.; Hou, X.; Sperger, T.; Schoenebeck, F.; Lautens, M. An Exclusively trans-Selective Chlorocarbamoylation of Alkynes Enabled by a Palladium/Phosphaadamantane Catalyst. Angew. Chem., Int. Ed. 2015, 54, 15897−15900. (27) Yin, G.; Kalvet, I.; Englert, U.; Schoenebeck, F. Fundamental Studies and Development of Nickel-Catalyzed Trifluoromethylthiolation of Aryl Chlorides: Active Catalytic Species and Key Roles of Ligand and Traceless MeCN Additive Revealed. J. Am. Chem. Soc. 2015, 137, 4164−4172. (28) Amatore, C.; Azzabi, M.; Jutand, A. Rates and mechanism of the reversible oxidative addition of (Z)- and (E)-1,2-dichloroethylene to low-ligated zerovalent palladium. J. Am. Chem. Soc. 1991, 113, 1670− 1677. (29) Amatore, C.; Jutand, A. Anionic Pd(0) and Pd(II) Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions. Acc. Chem. Res. 2000, 33, 314−321. (30) For selected previous computational studies that attempted to address this question, see: (a) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. Palladium Monophosphine Intermediates in Catalytic CrossCoupling Reactions: A DFT Study. Organometallics 2006, 25, 54−67. (b) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. The PalladiumCatalyzed Cross-Coupling Reaction of Carboxylic Anhydrides with Arylboronic Acids: A DFT Study. J. Am. Chem. Soc. 2005, 127, 11102− 11114. (c) Ahlquist, M.; Fristrup, P.; Tanner, D.; Norrby, P.-O. Theoretical Evidence for Low-Ligated Palladium(0): [Pd−L] as the Active Species in Oxidative Addition Reactions. Organometallics 2006, 25, 2066−2073. (31) Proutiere, F.; Schoenebeck, F. Solvent Effect on PalladiumCatalyzed Cross-Coupling Reactions and Implications on the Active Catalytic Species. Angew. Chem., Int. Ed. 2011, 50, 8192−8195. (32) Proutiere, F.; Schoenebeck, F. Orthogonal Selectivities under Pd(0) Catalysis with Solvent Polarity: An Interplay of Computational and Experimental Studies. Synlett 2012, 23, 645−648. (33) Schoenebeck, F.; Houk, K. N. Ligand-Controlled Regioselectivity in Palladium-Catalyzed Cross Coupling Reactions. J. Am. Chem. Soc. 2010, 132, 2496−2497. (34) Proutiere, F.; Lyngvi, E.; Aufiero, M.; Sanhueza, I. A.; Schoenebeck, F. Combining the Reactivity Properties of PCy3 and PtBu3 into a Single Ligand, P(iPr)(tBu)2. Reaction via Mono- or Bisphosphine Palladium(0) Centers and Palladium(I) Dimer Formation. Organometallics 2014, 33, 6879−6884. (35) Proutiere, F.; Aufiero, M.; Schoenebeck, F. Reactivity and stability of dinuclear Pd(I) complexes: studies on the active catalytic species, insights into precatalyst activation and deactivation, and application in highly selective cross-coupling reactions. J. Am. Chem. Soc. 2012, 134, 606−612. (36) Aufiero, M.; Scattolin, T.; Proutière, F.; Schoenebeck, F. AirStable Dinuclear Iodine-Bridged Pd(I) Complex - Catalyst, Precursor, or Parasite? The Additive Decides. Systematic Nucleophile-Activity

ACKNOWLEDGMENTS We are grateful for the financial support from the RWTH Aachen University, ETH Zü rich, MIWF NRW and the Evonik Foundation (doctoral scholarship to T.S.).

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Computation and Experiment: A Powerful Combination to Understand

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