MetalâLigand Bifunctional Catalysis: The âAcceptedâ Mechanism, the

Research Article pubs.acs.org/acscatalysis

Metal−Ligand Bifunctional Catalysis: The “Accepted” Mechanism, the Issue of Concertedness, and the Function of the Ligand in Catalytic Cycles Involving Hydrogen Atoms Pavel A. Dub* and John C. Gordon Chemistry Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States S Supporting Information *

ABSTRACT: For years, following the ideas of Shvo and Noyori, the core assumption of metal−ligand bifunctional molecular catalysis has relied on the direct involvement of the chelating ligand in the catalytic reaction via a reversible proton (H+) transfer through cleavage/formation of one of its X−H bonds (X = O, N, C). A recently revised mechanism of the Noyori asymmetric hydrogenation reaction (Dub, P. A. et al. J. Am. Chem. Soc. 2014, 136, 3505) suggests that the ligand is rather involved in the catalytic reaction via the stabilization of determining transition states through N−H···O hydrogenbonding interactions (HBIs) and not via a reversible H+ transfer, behaving in a chemically intact manner within the productive cycle or predominantly in a chemically intact manner within productive cycles. By reexamining selected examples of computational mechanistic studies involving bifunctional catalysts from the literature in the years between 2012−2017, the purpose of this work is to point out common misconceptions in modeling concerted reactions and show that the actual stepwise nature of key transition states unveils a more complicated catalytic reaction pool (all conceivable catalytic pathways and their crossovers). Such a realization can not only potentially result in a reconsideration of the “accepted” mechanism but also lead us to a new conceptual understanding of the role that the ligand plays in the reaction. The ultimate goal of this paper is, therefore, to encourage the reader to reconsider the function of the ligand in catalytic cycles of hydrogenation/dehydrogenation with bifunctional catalysts, which until recently has relied almost exclusively on a chemically noninnocent ligand. KEYWORDS: metal−ligand bifunctional catalysis, concerted reaction, metal−ligand cooperation, chemically noninnocent ligand, chemically innocent ligand, Noyori mechanism

1. INTRODUCTION 1

2

type M/NH bifunctional catalysts for large-scale reductions of CO and CN functionalities.19 Rational design, coupled with a trial-and-error approach and unique mechanistic principles have resulted in the continuous development of new bifunctional catalysts.20 From their initial discovery, the unique set of properties observed with bifunctional reduction catalysts in particular (high turnover efficiencies, high CO/CC chemo- and enantioselectivities) were traditionally associated with the direct participation of the ligand in catalytic reaction via a reversible H+ transfer through the cleavage/formation of one of X−H bonds (X = O, N, C). The reason for this has a posteriori nature manifested in numerous experimental observations from stoichiometric reactions studied by molecular spectroscopy and/or via product isolation, as well as the authoritative influence of the “accepted mechanism” of the most famous reaction with bifunctional catalysts, the Noyori

3

The discovery of organometallic complexes 1, 2−3, and 4 shown in Figure 1 resulted in the creation of a novel branch of homogeneous catalysis known as metal−ligand bifunctional catalysis.4 The field has rapidly developed, and it has become a general strategy for effecting highly efficient molecular transformations in synthetic organic chemistry in both academia and industry.5 Practical catalytic reactions span the chemo- and/or enantioselective hydrogenation and transfer hydrogenation of polar CO and CN functionalities,4,5,5j,k,n,o,r,s dehydrogenation of alcohols, carboxylic acids, and other substrates in various forms,4,5i,l,m,q as well as other important chemical transformations.4,5o,6 Companies within the fine chemical industry including Takasago Int. Corp.,7 Central Glass Co.,8 Merck,9 Mitsubishi Chemical Corp.,10 Pfizer,11 Johnson Matthey,12 Givaudan SA,13 Firmenich SA, 14 Boehringer Ingelheim Pharmaceuticals,15 DSM Innovative Synthesis,16 Enantiotech Corp.,17 and Zhejiang Jiuzhou Pharmaceutical Co.18 use Noyori© XXXX American Chemical Society

Received: June 1, 2017 Revised: August 14, 2017 Published: August 21, 2017 6635

DOI: 10.1021/acscatal.7b01791 ACS Catal. 2017, 7, 6635−6655

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Figure 1. Pioneering prototypes of M/OH, M/NH, and M/CH metal−ligand bifunctional catalysts.

asymmetric hydrogenation. Indeed, in performing NMR studies with 1−4 or similar bifunctional molecular catalysts, the transformations21,22 and reaction products shown in Figure 2 were typically observed in the mixture with other products (e.g., alkoxides).2f,3,23

Scheme 1. Classical Noyori Mechanism for the Hydrogenation of Ketonic/Aldehydic Substrates Is Based on Direct Participation of the Ligand in the Catalytic Reaction via a Reversible H+ Transfer through Cleavage/Formation of One of its X−H Bonds, and the Concerted Nature of Key Transition States TSa−TSc (X = O, N, C)a

Figure 2. Stoichiometric chemical transformations observed by NMR spectroscopy and/or via product isolation for M/XH bifunctional catalysts (X = O, N, C). The transition metal (M) is most-typically selected from Ru, Ir, Fe, Mn, Os, and Rh. a For simplicity, the formation of alkoxides, possible off-loop resting states, is not shown.

Although these stoichiometric transformations are performed under conditions inherently dif ferent from catalytic ones, the behavior of the ligand as “chemically non-innocent”5a,24 has been extrapolated to catalytic reactions themselves, for the first time by Shvo in 1985.1a,e Ten years later or so, Noyori proposed the key transition-states TSa−TSc for transformations involving ketones as substrates, and as a result, ketone hydrogenation, which is currently one of the largest-volume applications of bifunctional catalysts within the fine chemical industry for almost 20 years (1995−2014), was accepted to follow what can be termed as the classical Noyori mechanism shown in Scheme 1. Details have been discussed elsewhere.25 Within this catalytic cycle, cleavage of the H−H bond was traditionally postulated by chemists5b,e,f,22 to proceed through transition-states TSb or TSc. It is important to point out here, however, that in the presence of any molecule containing an O− H functionality (e.g., a protic solvent if used, a reaction product, a catalyst itself, or traces of water in the reaction mixture), cleavage of the H−H bond becomes computationally more favorable via TSc by >10−20 kcal·mol−1.26 In practice, this likely means that if

the minimum energy path (MEP)27 for a certain catalytic reaction with a particular molecular bifunctional catalyst indeed corresponds to the classical Noyori mechanism, the step in which the H−H bond is cleaved should rather be represented via TSc. In fact, the relative activation barrier for H−H bond cleavage via transition-state TSb is computed to be in the range of 20−30 kcal· mol−1 for different bifunctional catalysts,5a,28 suggesting that transformations involving molecular H2 in Figure 2 are instead most likely catalyzed by water (or other protic solvent molecules present), and/or a quantum tunneling effect is involved.5a Traces of water present in NMR experiments or during organometallic syntheses, convincingly explain why the reported addition of molecular hydrogen H2 to all three types of 16e− -one or -amido complexes, as shown in Figure 2, spans a broad reaction rate range manifested by temperature/time from −80 °C within a few minutes,23d up to 25 °C within a few minutes to hours;2f,3 the more water that is present in the system, the faster the reaction. 6636


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ACS Catalysis In contrast, stoichiometric reactions between the 18e− hydrido complexes and ketonic/aldehydic substrates in (or the reverse reactions between the 16e− complexes and alcoholic substrates) are reported to take place at room temperature within mixing and up to ∼10 min time suggesting that (1) water does not significantly affect the reaction rate, as expected, and (2) the ease of N−H group deprotonation under stoichiometric conditions.2f,23a,29 Therefore, the key transition states in the classical Noyori mechanism are multibond concerted30 TSa and TSc.31 In recent years, more advanced computational techniques such as Car− Parrinello molecular dynamics (CPMD)32 and density functional theory (DFT)33 incorporating solvent effects, independently suggested that the nature of TSa34 and TSc34a as multibond concerted stoichiometric transformations have no mechanistic relevance in solution for the Noyori and Noyori−Ikariya M/NH catalysts, wherein the same reactions proceed stepwise through high-energy ion-pair intermediates as shown in Scheme 2, gray circles.5a

appear35 within the catalytic cycle leading to the conventional Noyori mechanism36,37 (Scheme 3). On the other hand, the existence of new intermediates along the catalytic reaction potential energy surface (PES), which is always multidimensional,38 could mean the potential existence of alternative reaction channels to deliver the reaction product and regenerate the catalyst. A schematic representation of this statement is provided in Figure 3.

Scheme 2. Issue of Concertedness for the Determining Transition State(s) in the Hydrogenation of Ketones (or the Microscopically Reverse Dehydrogenation of Secondary Alcohols) with M/XH Bifunctional Catalysts Figure 3. Schematic representation of what the realized stepwise nature of key transition states means for an understanding of the Noyori asymmetric hydrogenation reaction. The yellow route corresponding to the “accepted” mechanism represents one possibility among others to deliver the reaction product and regenerate the catalyst. The set of green routes represent alternative more energetically favorable paths.

In the classical interpretation of the Noyori asymmetric hydrogenation reaction, the reaction can only proceed via one reaction channel, the yellow route in Figure 3. The existence of new intermediates on the PES adds more routes and their intersections (crossovers). Noyori−Ikariya transfer hydrogenation34b and Noyori hydrogenation34a are so far the only two ketone reduction catalyst systems where all possible (at least to the authors’ knowledge) reaction channels, and their crossovers have been computed and taken into account.5a For the Noyori hydrogenation reaction in propan-2-ol,34a for example, gauging

On one hand, the issue of concertedness does not change the core assumption of metal−ligand bifunctional molecular catalysis, since only more transition states and intermediates

Scheme 3. Conventional Noyori Mechanism36,37 for the Hydrogenation of Ketonic/Aldehydic Substrates with Bifunctional Catalysts Is Based on a Chemically Non-Innocent Ligand and Concerted or Step-Wise Nature of Key Transition States (L = O, N, or C)a

a

For simplicity, the formation of alkoxides, possible off-loop resting states, is not shown. 6637


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Scheme 4. Revised Mechanism of the Noyori Asymmetric Hydrogenation Reaction in Propan-2-ol under Base-Free Conditionsa

a See ref 5a. There are four ωB97X-D/SDD(Ru)/6-31G*(C,H,N,O,P)/SMD(propan-2-ol) feasible possibilities34a to deliver the product and two to regenerate the catalyst gauging “computational DFT accuracy”39 to be ∼3 kcal·mol−1.

“computational DFT accuracy”39 to be ∼3 kcal·mol−1, the MEP does not correspond to the conventional Noyori mechanism, but rather to a set of catalytic cycles I−IV, as shown in Scheme 4.5a Within this revised mechanistic picture for the Noyori asymmetric hydrogenation reaction, there are four computationally feasible possibilities to deliver the product and two to regenerate the catalyst as shown in Scheme 4. In the first step of each of the cycles I−IV, reduction of a ketonic/aldehydic substrate takes place within the outer-sphere through TSd, explaining both high turnover efficiencies and CO/CC chemoselectivities. In each case, the ligand is involved in the catalytic reaction via stabilization of determining transition-states TSd−TSf through N−H···O HBIs, but only one (cycle no. IV) among the four possibilities proceeds via a single step that is based on a chemically noninnocent ligand. Neglecting “accepted computational DFT accuracy”39 as ∼3 kcal·mol−1, which is often based on experimental results whose accuracies are also quite often unexamined, suggests that the major product delivery and catalyst regeneration proceeds via catalytic cycle I, one based on a cooperative5a,24 and chemically innocent5a,24 ligand. Within this so-called major cycle, the key intermediates are the trans-dihydride complex, the η2-H2complex, and the dihydrogen-bonded complex. In the presence of high concentrations of inorganic base (e.g., KOH, tBuOK,

etc), the same catalytic cycle is likely dominant, except the N−H functionality is thought to be replaced by a corresponding N−K one.23g,34a,40 A similar cycle based on a cooperative and chemically innocent ligand was established for the Ru-MACHO-catalyzed hydrogenation of esters, although the reaction pool is more complicated due to the nature of the substrate.8,41 A complete analysis of the catalytic reaction pool with Noyori−Ikariya transfer hydrogenation34b and Noyori hydrogenation catalysts34a resulted in several fundamental conclusions; (1) the mechanism of ketone reduction with these catalysts is of a much more sophisticated nature than is commonly accepted; (2) there are multiple reaction channels and their crossovers possible (two for transfer hydrogenation and five for hydrogenation, respectively); (3) the N−H group may or may not be involved in the catalytic reaction via its cleavage/formation in these channels, but always serves to stabilize the determining transition states via N−H···O HBIs; (4) the MEP for the Noyori asymmetric hydrogenation reaction in propan-2-ol does not proceed via the conventional Noyori mechanism and corresponds to the set of cycles I−IV shown in Scheme 4, in which, neglecting the degree of accuracy of DFT of ∼3 kcal·mol−1, the major contribution to product delivery and catalyst regeneration proceeds via catalytic cycle I, based on a chemically innocent ligand, and; (5) as a result of (4), there could be catalysts operating in an outer-sphere42 6638


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Figure 4. Classification of concerted organometallic reactions based on the number of bond-breaking and bond-forming processes as well as synchronicity/asynchronicity (relative terms used to describe “events” during a concerted process, see text).

fashion in which alkylation of the N−H functionality may lead to beneficial properties (high turnover efficiencies, high CO/ CC chemo- and perhaps enantioselectivities) under certain conditions,37,43 or coordinatively saturated catalysts lacking N− H functionalities speculatively operating through the same reaction channels or perhaps one major channel (i.e., I in Scheme 4).44 Although some of these conclusions were independently realized, at least in part, for a few other M/NH8,45 and M/CH46 bifunctional catalysts, a significant number of scientific contributions in which the mechanism of hydrogenation/ dehydrogenation catalyzed by bifunctional catalysts is being studied, focus solely on computing catalytic cycles that are based on the cleavage/formation of X−H bonds.5a The error of such an approach is obvious: instead of actually studying the mechanism of the catalytic reaction, which requires consideration of all channels possible in such reactions and further identification of the MEP (and only then with recalibration of experimental data), statements such as “the reaction mechanism was studied”, “computed”, “confirmed by calculations”, among others, are made. By analyzing some of the recent literature, our attention was drawn to the issue of concertedness for the key transition states with bifunctional catalysts. Here we would like to point out some typical assignment errors that occur in the computational modeling of concerted reactions that can potentially lead to wrong conclusions being made. The purpose of this work is to show that the realized stepwise nature of key transition states could not only necessitate the reformulation of the reaction mechanism but also bring us to a different understanding of the conceptual role of the ligand involved in catalytic reactions with bifunctional catalysts.

Figure 5. Three possible mechanisms for cyclobutane cracking. The free energy (y-axis) is not scaled. Adapted with permission from ref 48a. Copyright 1974 American Chemical Society.

Scheme 5. Pyrrole-Derivative Synthesis Using the Acceptorless Dehydrogenative Coupling of Amino Alcohols with Secondary Alcohols Reported by Milstein and CoWorkers in 201355

nous.30,48 The former is one in which all of the bond-making and bond-breaking processes take place in unison, having all proceeded to comparable extents in the transition state.48a An asynchronous concerted reaction is one where some of the changes in bonding taking place in the first part of the reaction, followed by the rest.30 As the degree of asynchronicity is always relative, Dewar further discussed that multibond reactions cannot normally be synchronous.30 Nevertheless, in gas-phase calculations, based on analysis of the displacement vector corresponding to the imaginary frequency, TSII is relatively synchronous,49 whereas TSIII and TSIV are relatively asynchronous (one of two hydrogen atoms are transferred relatively more).50 Solvent can further contribute to the asynchronicity of the reaction to the extent of a stepwise process (e.g., the appearance of an intermediate on the PES).51 For decades, many experimental and theoretical studies of simple organic reactions have been aimed toward distinguishing between the concerted or stepwise nature of multibond reactions.52 The classic example is three mechanisms of cyclobutane cracking as shown in Figure 5.

2. RESULTS AND DISCUSSION 2.1. The Issue of Concertedness. IUPAC defines a concerted reaction as a single-step reaction through which reactants are directly transformed into products (i.e., without the involvement of intermediates).47 Depending on the number of bond-breaking and bond-forming processes, concerted organic reactions were classified by Dewar into one-bond concerted and multibond concerted,30 respectively. Such a terminology can arguably be expanded to organometallic systems. For example, one-bond concerted reactions, or simply one-bond reactions, involve the breaking of one bond and the formation of one bond, transition-state TSI37 in Figure 4. A multibond concerted reaction involves the breaking of multiple bonds and the formation of the same number of bonds as shown in Figure 4, transition-states TSII−TSIV. Depending on the simultaneity of electronic reorganization, concerted multibond reactions are classified as synchronous and asynchro6639


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Scheme 6. Reported Gas-Phase Computed Mechanism of the Dehydrogenation of 1-Phenylethanol 7 into Acetophenone 9 with Milstein Ru (Pre)Catalyst 555

Scheme 9. Reported Gas-Phase and Continuum Methanol Computed61 for the First Step of the Mechanism of Hydrogenation of Nitriles Described by Beller59

Figure 6. IRC path for the gas-phase reaction between 6 and two molecules of 7 in Scheme 6 computed in this work at the DFT/M06/ SDD(Ru)/6-31G**(C,H,N,O,P) level of theory. For the optimized transition-state structures, noncritical H atoms are omitted for clarity. E = electronic energy.

Scheme 7. Hydrogenation of Nitriles Reported by Beller and Co-Workers in 201459

Figure 7. IRC path for the reaction between 15 and acetonitrile 16 in Scheme 9 computed in this work at the DFT/B3PW91/LANL2DZ(Ru)/TZVP(all other)/PCM(MeOH) level of theory. For the optimized transition-state structures, noncritical H atoms are omitted for clarity. E = electronic energy.

Scheme 8. Proposed and Computed by Beller and CoWorkers (Noyori Classical) Mechanism of Nitriles Hydrogenation59

Scheme 10. Transformation of Primary Alcohols into the Corresponding Carboxylic Acidsa with Milstein’s Ru (Pre)Catalyst66

a

The product is obtained after acidic workup.

Early extended Hückel theory gas-phase computations of Hoffmann (1970) provided the PES corresponding to scenario (a) in Figure 5.53 Twenty-five years later, however, Zewail used 6640


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Scheme 11. Reported Gas-Phase Computed Mechanism of the Dehydrogenation of Gem-Diol 21 into Butyric Acid 22 with Milstein’s Ru (Pre)Catalyst67

alternative reaction path or paths (or branching). As was discussed earlier, the realization of such branching for the Noyori−Ikariya transfer hydrogenation34b and Noyori hydrogenation catalysts34a led to the reformulation of the corresponding reaction mechanisms.5a 2.1.1. Why Should One Not Neglect Intrinsic Reaction Coordinate (IRC) Calculations? Catalytic pyrrole syntheses using the acceptorless dehydrogenative coupling of amino alcohols with secondary alcohols (equivalent amounts), catalyzed by the ruthenium pincer complex 5 and base has been reported by Milstein and co-workers in 2013 (Scheme 5).55 The mechanism of this reaction has subsequently been studied computationally by Wang and co-workers along the gas-phase PES at the DFT/M06/SDD(Ru)/6-31G**(C,H,N,O,P) level of theory.56 Following the “accepted mechanism”, it was assumed that the key intermediate that dehydrogenates 1-phenylethanol 7 into acetophenone 9 (i.e., one of the steps in this multistep catalytic reaction) is the 16e− Ru amido complex 6 as shown in Scheme 6. It was reported that this reaction proceeds via a multibond concerted transition-state TS1* involving one “shuttle” molecule, the importance of which was even highlighted in the title of the work.56 Herein we performed frequency and IRC57 calculations upon the published geometry of the transition-state TS1* at the same level of theory.58 We found that the claimed identity of TS1* as a concerted multibond transition structure is incorrect. The corresponding first-order saddle point (i1376 cm−1) represents TS1 in Figure 6, in which only proton transfer along the C···H···O coordinate takes place connecting intermediates 10 and 11, respectively. Further analysis of the IRC-path shows that the overall process takes place via two more transition-states TS2−TS3 and intermediates 12 (two isomers from the IRC-calculations, see SI) and 13 connecting them. In other words, the same reaction is actually stepwise, even within the gas-phase profile. In another example reported in 2014, Beller and co-workers described the selective hydrogenation of nitriles with a welldefined iron pre(catalyst) 14,59 which should be regarded as the modification of Kuriyama’s original Ru catalyst,60 Scheme 7. The authors mentioned that they “became interested in elucidating the possible reaction mechanism for this nitrile reduction” and computed both a Schrock−Osborn inner-sphere mechanism and a classical Noyori mechanism for this reaction in the gas-phase.59 Because of the unsurprising energetic preference of the latter case, the reaction mechanism was proposed as shown in Scheme 8. Later in 2016, Jiao presented more computational details on this reaction, which was now studied with the inclusion of solvent effects and even compared for three different metals (M = Fe, Ru and Os) under DFT/B3PW91/LANL2DZ(Fe,Ru,Os)/TZVP-

Figure 8. IRC path for the reaction between butyric acid 22 and 8 in Scheme 11 computed in this work at the DFT/ωB97XD/SDD(Ru)/631G*(C,H,N,O,P) level of theory in the gas-phase, implicit and implicit/explicit solvent (SMD model). For the optimized transitionstate structures, noncritical H atoms are omitted for clarity. E = electronic energy.

femtosecond transition-state spectroscopy with the time resolution of 10−15 seconds and detected a high-energy diradical intermediate consistent with the PES corresponding to scenario (c) in Figure 5.54 In a catalytic reaction, the issue of concertedness is particularly important. Indeed, the presence of any intermediate along the catalytic reaction coordinate, even of high potential energy and/or short lifetime, potentially means an 6641


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ACS Catalysis Scheme 12. Two Microscopically Reverse Reactions Studied Computationally†

† (a) Computed by Wang and co-workers at the DFT/TPSSTPSS/LanL2DZ(Ru)/6-31G**(all others) level of theory.70 Adapted with permission from ref 28. Copyright 2015 American Chemical Society; (b) computed by Yang at the ωB97XD/6-31++G**/SMD(EtOH) level of theory.46a Actual catalyst: R = iPr, computed R = Me. Adapted with permission from ref 28. Copyright 2015 American Chemical Society.

Figure 9. Catalytic reaction pool for M/XH bifunctional catalysts (X = O, N, C) for the case when determining transition state(s) in the hydrogenation of ketones (or microscopically reverse dehydrogenation of secondary alcohols) are of a concerted nature. For simplicity, the arrows correspond to the forward (hydrogenation) reaction only.74 6642


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Figure 10. Catalytic reaction pool for M/XH bifunctional catalysts (X = O, N, C) for the case when determining transition state(s) in the hydrogenation of ketones (or the microscopic reverse dehydrogenation of secondary alcohols) are of a stepwise nature. For simplicity, the arrows correspond to the forward (hydrogenation) reaction only.74

(all other)/PCM(MeOH) level of theory.61 In all three cases, the first step of the reaction was reported to proceed via a multibond concerted transition-state TS5* that connects proposed intermediates 15/16 and 17 as shown in Scheme 9. Herein we have performed frequency and IRC calculations upon the published geometry of the transition-state TS5* under the same level of theory (M = Ru). Similarly to the first example discussed in this paper with the Milstein catalyst (vide infra), it was found that the claimed identity of TS5* as a concerted multibond transition structure, is in fact incorrect.62 The corresponding first-order saddle point (i1094 cm−1) actually represents TS5 in Figure 7, in which only proton transfer along the N···H···N coordinate takes place connecting well-defined intermediates 19 and 20, respectively. Further analysis of the IRC path shows that the overall reaction proceeds via one more transition-state TS4, and intermediate 18. We would ask the same question again: is the issue of concertedness important? We believe that this issue should not be neglected, because alternative reaction channels can be possible as discussed above. We would also like to point out that the experimental observation in which the N−H group within a catalyst was replaced with an N−Me fragment leading to a totally

inactive catalyst,59 should not necessarily be used as an argument to state that the reaction “must proceed” via N−H bond cleavage/formation.37 2.1.2. Gas-Phase versus Computations with the Inclusion of Solvent Effects. There have been many reviews written on this topic.63 Despite this, it would appear that many researchers prefer to compute reaction mechanisms in the gas-phase. There are many reasons for this, and it is not our purpose to list them here. Herein, however, we would like to demonstrate how the inclusion of solvent effects can dramatically change not only the issue of concertedness for one particular step of the reaction but also arguably the understanding of the overall reaction mechanism as well.64 In 2013, Milstein’s group applied the same Ru (pre)catalyst 565 discussed in the previous section in the catalytic transformation of primary alcohols into carboxylic acid salts and H2 using water as the −OH group source (Scheme 10).66 The following year, Li and Hall studied this reaction computationally at the DFT/ωB97XD/SDD(Ru)/6-31G**(C,H,N,O,P) level and in the gas-phase,67 despite the fact that the reaction is carried out in one of the most polar solvents, NaOH-based water.68 Following the “accepted mechanism”, it 6643


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Figure 11. Dependence of the computed energy difference between TSe and TSf for the Noyori catalyst trans-[RuH2{(S)-binap}{(S,S)-dpen}] on the nature of functional, basis set, and continuum model used in this work. Ultrafine grid is used in all the computations. For more details, see SI.

apparently multistep catalytic reaction, is the 16e− Ru amido complex 6 as shown in Scheme 11.

was assumed that the key intermediate that dehydrogenates gemdiol 21 into butyric acid 22, one of the proposed steps in this 6644


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ing to the imaginary frequency reveals a very asynchronous movement of hydride and proton hydrogen atoms, respectively. As shown in the middle part of Figure 8, nonspecific solvation of water further contributes to the asynchronicity of this reaction to the extent of a stepwise process: in continuum water, the same reaction proceeded via two transition-states TS7 (i764 cm−1) and TS8 (i1436 cm−1), and a detectable ion-pair intermediate 26 connecting them. It is interesting to note that TS7 is stabilized by apparently weak C−H···O hydrogen bonding interaction (dH···O = 2.64 Å), in contrast to, for example, a much stronger N−H···O hydrogen bonding interaction observed with Noyori-type M/ NH bifunctional catalysts (dH···O ∼ 2.0 Å).37 In the ion-pair intermediate 16, the C−H···O hydrogen bonding is almost absent (dH···O = 2.73 Å). The most interesting result is obtained when eight explicit water molecules are further added to the computations at the H-bonding positions around the CO functionality and the “reactive” C−H group of the Ru catalyst, lower part of Figure 8, respectively. The first step of the reaction proceeds similarly via an outer-sphere hydride transfer, but the relative activation barrier lowers by ∼5 kcal·mol−1 (transitionstate TS9; intermediate 28 and two intermediates 29 from the IRC). In the second step of the reaction, the source of the proton could be the C−H functionality per mainstream thinking

Scheme 13. Morris Asymmetric Hydrogenation Reaction with the trans-[RuH2{(R)-binap}{tmen}] Catalyst5e,f

The reaction was reported to proceed via a concerted multibond transition-state structure TS6. Assuming the validity of the principle of microscopic reversibility,69 herein we have recalculated the reverse reaction at the same level of theory, except without adding polarization functions to the hydrogen atoms, and performed IRC-computations as shown in upper part of Figure 8. Indeed, in the gas-phase, according to IRC calculations, the reaction proceeds as correctly reported by Li and Hall via multibond concerted transition-state structure TS6 (i1337 cm−1). However, analysis of the displacement vector correspond-

Figure 12. Catalytic reaction pool for the Morris asymmetric acetophenone hydrogenation reaction with trans-[RuH2{(R)-binap}{tmen}] catalyst,23b,29,84 this work.74 Abbreviations: δ = delta configuration of the five-membered tmen ring used in the original work based on X-ray structure.23b se = symmetrical envelope configuration of the five-membered tmen ring.41 6645


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Figure 13. Dependence of the free-energy difference between TSb and TSe with the Morris trans-[RuH2{(R)-binap}{tmen}] catalyst on functional, basis set, and continuum solvent model used in this work. Abbreviations: δ = delta configuration of the five-membered tmen ring, generalized gradient approximation (GGA), m (meta), hybrid (h), range-separated hybrid (RSH). Ultrafine grid is used in all the computations. For more details, see SI.

presented in this section with the M/CH catalyst suggest that hydrogenations/dehydrogenations using Milstein-type catalysts can unequivocally proceed via a chemically innocent ligand.46a,b 2.2. Two Catalytic Reaction Pools for Bifunctional Catalysts in the Hydrogenation of Ketones/Dehydrogenation of Secondary Alcohols. In 2012 Wang reported a computational study70 focused on the mechanism of selective,

(transition-state TS10; intermediate 30), or solvent (transitionstate TS11; intermediate 31). According to our computations, the reaction proceeds via the second option, and the overall process is ∼20 kcal·mol−1 more favorable! Therefore, inclusion of solvent effects not only suggests that the reaction is stepwise but also potentially changes our understanding about the actual role of the ligand and the overall reaction mechanism. Calculations 6646


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within the revised mechanism of the Noyori hydrogenation reaction.34a A notable difference between these cycles lies in whether or not the ligand is involved in the catalytic reaction via cleavage/formation of C−H bonds. According to the principle of microscopic reversibility,69 the reaction should proceed through the same transition states, and therefore, only one catalytic cycle should be relevant. Which one? This brings up the issue of how do we really study catalytic hydrogenation reactions with even the simplest substrates (e.g., ketones) with bifunctional catalysts? As discussed in the Introduction, the issue of concertedness for the determining transition state(s) has dramatic effects on the nature of the catalytic reaction pool and the identity of the MEP with Noyori and Noyori−Ikariya catalysts.5a We envision two reaction pools that are illustrated below in two graph-type diagrams that are projections of free energy on a 2D surface, depending on the issue of concertedness of determining transition states (Scheme 3).73 If the transition state is indeed suggested to be concerted by computations involving all possible solvent effects, the reaction pool is likely represented by only one reaction channel (only one possibility to generate the reaction product for the forward hydrogenation reaction) known as the classical Noyori mechanism and shown in Figure 9. Unless at minimum, quantum tunneling is involved, catalyst regeneration proceeds via TSe−TSf, and not metal−ligand cooperation TSb. However, if TSa dissects into two transition states including TSd and an intermediate connecting them, then the catalytic reaction pool converts into multiple reaction channels and their crossovers (five possibilities to produce the reaction product), as shown in Figure 10.

Figure 14. What the revised mechanism of the Noyori asymmetric hydrogenation reaction34a means for future catalyst design.

catalytic imine formation from alcohols and amines described by the Milstein group.71 The catalytic cycle corresponding to the proposed first step of the reaction, alcohol dehydrogenation, is adapted in Scheme 12a. Details have been explained elsewhere.28,70 One year prior to this, another computational study46a from Yang devoted to the mechanism of the reverse reaction corresponding to the ketone hydrogenation catalyzed by an isostructural Fe (pre)catalyst from Milstein’s group, was reported.72 The corresponding computed catalytic cycle is reproduced in Scheme 12b. Details have been discussed elsewhere.28,46a The cycle shown in Scheme 12a represents the conventional Noyori mechanism.36,37 In contrast, the catalytic cycle shown in Scheme 12b corresponds to the major cycle

Figure 15. Rationalization of “negative” and “positive N−H effects” based on the revised mechanism of the Noyori asymmetric hydrogenation reaction.37 Only one determining transition state corresponding to outer-sphere hydride transfer is shown. 6647


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Figure 16. Recent examples of well-defined M/NH catalysts with a “positive N−H effect”.

used, being on average ∼3.5 kcal·mol−1 on the free energy and ∼5 kcal·mol−1 on the electronic energy scale in favor of TSe, respectively. The most sophisticated method in terms of basis set, ωB97X-D/bss1, predicts a value of 6.2 kcal·mol−1 on the electronic energy scale, corresponding to ∼40 000 times faster product delivery via catalytic cycle I. Figure 11 also shows that the old hybrid generalized gradient approximation (hGGA) B3LYP77 and mPW3PBE78 functionals which are not dispersion corrected, and even the parametrized hGGA M0679 predict slightly opposite trends in stabilities between TSe and TSf, an average of ∼ − 0.3 to −3 kcal·mol−1. The trend is recovered when Grimme’s D3 dispersion model80 is further added into calculations. For example, B3LYP-D3 and M06-D3 predict an average of ∼2 kcal·mol−1 and ∼1.2 kcal· mol−1 energy difference in favor of TSe respectively. Similarly, an average of ∼3 kcal·mol−1 energy difference in favor of TSe is observed with the relatively newer metaGGA MN12L functional,81 which, however, is a “pure” functional (i.e., does not include Hartree−Fock exchange to address the self-exchange problem of DFT)82 and is arguably less accurate (being the third rung on Jacob’s ladder39,82). In any case, all of these numbers are within the above-mentioned accuracy of DFT,39 and it is obvious that, computationally, catalytic cycle I is either concurrent with the set of cycles II−IV shown in Scheme 4, or dominant, based on dispersion-corrected functionals. Experimentally, ∼5% deuteration of the reaction product is observed at the benzylic position when the Noyori hydrogenation reaction is carried out in propan-2-ol-d8, regardless of in the presence or absence of base.83 This suggests that only some small participation of the solvent in the reaction occurs and led us to conclude, together with results obtained with dispersion-corrected functionals in previous work and supported by this work, that the major catalytic cycle within the Noyori hydrogenation reaction is catalytic cycle I in Scheme 4, based on upon a cooperative and chemically innocent ligand.

Although the reaction pool in Figure 10 looks rather complicated, the real picture is even more so, since each point on the PES has different conformers, each of which can, in addition, undergo potential NH/NK exchange under high t BuOK concentration,23g,34a,40 exponentially increasing the number of species to consider. Despite these difficulties, there is no need to compute all intermediates and transition states, because after outer-sphere (enantioselective) hydride transfer, the fate of the reaction will be determined solely by the relative energies of three transition-states TSb, TSe, and TSf, corresponding to the cleavage of the H−H bond. For example, for the Noyori asymmetric hydrogenation reaction in propan-2-ol studied at the ωB97X-D/SDD(Ru)/6-31G*(C,H,N,O,P)/ SMD(propan-2-ol) level of theory, TSe is more favorable than TSf by ∼3 kcal·mol−1, and in turn much more favorable then TSb by ∼20 kcal·mol−1 on a free-energy scale.34a Assuming that “computational DFT accuracy”39 is ∼3 kcal·mol−1 and analyzing Figure 10, this suggests that there are four computationally feasible possibilities with which to deliver the product and two to regenerate the catalyst in the Noyori asymmetric hydrogenation reaction as was shown earlier in Scheme 4. Only one among these four possibilities proceeds via chemically noninnocent ligand, however. The actual degree of product delivery in the Noyori asymmetric hydrogenation reaction is determined kinetically via the energy difference between TSe and TSf. If one assumes ∼3 kcal·mol−1 free-energy difference under standard conditions between these transition states (e.g., as actually computed) and that “computational noise”39 is neglected, the product is delivered ∼150 times faster via catalytic cycle I then via combined channels II−IV ending at TSf (Scheme 4). Figure 11 further shows that the energy difference between TSf and TSe using the range-separated hybrid (RSH) ωB97X-D functional,75 incorporating Grimme’s D2 dispersion model76 does not significantly depend on the basis set and/or continuum model 6648


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ACS Catalysis

Scheme 14. A Suggested Productive Set of Catalytic Cycles of Hydrogenation for Some M/NR Molecular Catalysts (R = H or Alkyl)a

a

For R = H, in the presence of high inorganic base such as KOH, tBuOK, MeONa, etc., N−H can be formally replaced by N−K, N−Na.

much newer highly parametrized including dispersion corrected hGGA or RSH functionals predict a ∼20 kcal·mol−1 energy difference under standard conditions, suggesting that even if quantum tunneling is involved in H−H cleavage via metal− ligand cooperation TSb, the reaction will still not proceed through this reaction channel, because the corresponding neutral η2-H2-complex is typically located ∼10 kcal·mol−1 below TSb.86,87 The results presented in this section suggest that the Morris asymmetric ketone hydrogenation reaction with the trans[RuH2{(R)-binap}{tmen}] catalyst actually proceeds via the same revised mechanism for the Noyori hydrogenation reaction in an aprotic solvent which is based on a cooperative, but chemically innocent ligand. With this background, it is now possible to reconsider41 stoichiometric NMR experiments,

What happens if the same reaction is carried out in an aprotic solvent? Let us discuss one more catalytic reaction23b,29,84 that is currently accepted to follow the classical Noyori mechanism,5e,f Scheme 13. Because this reaction is carried out in an aprotic solvent, the catalytic reaction pool is significantly simpler than the one introduced in Figure 10. Indeed, after the outer-sphere hydride transfer through TSd,85,41 the fate of the reaction is determined only by the energy difference between TSe and TSb, Figure 12. Figure 13 further shows that regardless of functional, basis set, and continuum model used, TSe is always energetically more favorable over TSb by 5−20 kcal·mol−1. The lower limit of ∼5 kcal·mol−1 is observed in the case of the 25 and 20 year old hGGA B3LYP77 and mPW3PBE78 functionals, respectively. The more recent but less-sophisticated third Jacob’s ladder39,82 rung metaGGA MN12L functional,81 predicts ∼12 kcal·mol−1. The 6649


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ACS Catalysis Scheme 15. “Inverse Catalyst Design” of M/NH Catalysts

these bifunctional catalysts could arguably be used in future molecular catalyst design, Figure 14. Since 1995 dozens of attempts have been made to alkylate the N−H functionality contained within M/NH Noyori-type catalysts.37 The resultant catalysts were typically either totally or almost inactive. The revised mechanism of the Noyori hydrogenation reaction well rationalizes these “negative N−H effects”, Figure 15a. Alkylation of the N−H functionality will not only destroy favorable HBIs within determining transition states in such cases but also increase the steric encumbrance around the hydride atom leading to catalyst−substrate repulsion and overall double destabilization. As a result, the reaction can still proceed, but kinetically much slower, depending both on the nature of the catalyst and substrate used as well as the conditions employed. In the past few years, at least 4 examples of well-defined 18e− saturated (pre)catalysts were reported37,43 in which alkylation of the N−H functionality leads to beneficial turnover, Figure 16.89,90 The revised mechanism of the Noyori hydrogenation reaction also rationalizes the “positive N−H effect” seen with these catalysts. Case (b) in Figure 15 represents the situation when the HBI is initially absent within M/NH catalysts. These allows for the alkylation of the N−H functionality without loss in turnover efficiency and the same high CO/CC chemoselectivity.37,43d Case (c) in Figure 15 represents a hypothetical situation in which HBIs likely exist within M/NH catalysts, but the catalytic reactions may still work for the alkylated cases, due to the absence of any catalyst−substrate repulsions, as a result of the possibility for such catalysts to adopt a sufficiently wide H−M− N−alkyl dihedral angle. For example, de Vries reported that upon methylation of the N−H functionality of the Ru (pre)catalyst complex supported by the tridentate NNS ligand, the latter changes its conformation from mer to fac.43b The corresponding dihedral angle Cl−Ru−N−H of ∼0.28° widens to ∼61.42° in the corresponding Cl−Ru−N−Me fragment (X-ray). Both (pre)catalysts reduce aldehydes with appreciable turnover efficiencies and CO/CC chemoselectivities.43b Finally, case (d) in Figure 15 represents a special case involving CO2 as a substrate or product. The reaction with the alkylated catalyst may either work,43c,f,g or not,91 depending on the conditions used. We suggested that the reason why it works is likely associated with one or more of these factors: (1) CO2 is one of the smallest

kinetics, H/D labeling experiments available for this catalyst.23b,29,84 We conclude this section with the fact that the presently accumulated data suggests that ketone hydrogenation using Shvo-type M/OH catalysts23a,26a,c,49 seems to operate via the reaction path we show in Figure 9, whereas Figure 10 likely represents the catalytic reaction pool with Noyori-type M/NH and Milstein-type M/CH catalysts. There are two fundamental differences between M/OH versus M/XH catalysts (X = N, C); (1) formal metal−ligand cooperation is accompanied by a change in the oxidation state of the metal within the Shvo catalyst from +2 to 0 or vise-versa; and (2) the acidity of the ligand decreases in the order OH > NH > CH. These two factors could be responsible for the direct involvement of the O−H functionality in the catalytic reaction via its bond cleavage/ formation and perhaps the concerted nature of key transition states. Obviously, hydrogenation of carbonyl substrates such as esters and carboxamides (or their microscopic reverses) will include even more reaction channels,88 making their complete study much more complicated, and therefore, they are not discussed in the present paper. 2.3. What Does the Revised Mechanism of the Noyori Asymmetric Hydrogenation Reaction Mean for Future Catalyst Design? Revised mechanisms for the Noyori hydrogenation34a and Noyori−Ikariya transfer hydrogenation reactions34b and that established for the Ru-MACHO-catalyzed ester hydrogenation,8,41 suggest that the ligand is involved in the catalytic reaction not via a reversible H+ transfer but rather via a stabilization of determining transition states via N−H···O hydrogen-bonding interactions. For the Noyori hydrogenation reaction34a and, to some extent, the related hydrogenation of esters with the Ru-MACHO catalyst in protic solvents,8,41 according to computational analyses and other assumptions discussed above, these reactions proceed with net retention of the N− H f unctionality. Protic solvent participation in these two reactions could enable some product delivery and/or catalyst regeneration via the cleavage/formation of N−H bonds of the ligand, but this contribution seems to be very small, almost negligible, especially under basic conditions. In aprotic solvents (e.g., in the abovementioned Morris asymmetric hydrogenation), product formation and catalyst regeneration seem to proceed exclusively with net retention of the N−H functionality. The realization of chemical innocence of the ligand during catalytic reaction with 6650


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ACS Catalysis

Scheme 16. A Suggested Productive Set of Catalytic Cycles of Hydrogenation for some M/NH Molecular Catalystsa

a

In the presence of high inorganic base such as KOH, tBuOK, MeONa etc., N−H can be formally replaced by N−K, N−Na.

H functionalities44 or for M/NH catalysts with wide torsion H− M−N−H angles,37 including one case when there is no direct metal−NH bonding.43a,d,e However, if there is the further possibility to stabilize the determining transition states via N− H···O HBIs, a catalyst will always use this avenue as shown in Scheme 15. Assuming no catalyst decomposition, HBIs are expected to enhance the efficiency of such metal−ligand bifunctional catalysts. They will operate through the same set of cycles, having one more possibility, IV, to deliver the product via a chemically noninnocent ligand due to crossover of the reaction pathways, or depending on the energy difference between TSe and TSf, one single cycle as shown in Scheme 16. Cycles I through III are united by the general term “H−/H+ outer-sphere hydrogenation mechanism”,5a or simply “H−/H+ mechanism” to show the sequence of events based on a chemically innocent ligand, wherein H− is transferred in the

carbonyl substrates, a 1D molecule; (2) it forms much weaker HBIs within determining transition states; and (3) possible higher catalyst stability under typically harsh conditions involving CO2 as a substrate/product.37 All of the alkylated catalysts shown in Figure 16 exhibit similar properties to the Noyori catalyst; 1) high turnover numbers (TON’s), and; b) high CO/CC chemoselectivities. We believe that these two factors are simultaneously due to the fact that the reduction of the carbonyl functionality takes place in the outer-sphere,42 following catalyst regeneration through the η2-H2 and the dihydrogen-bonded complexes via a similar set of cycles I−III, or one major cycle I as recently revised for the Noyori asymmetric hydrogenation reaction, Scheme 14. The relative contributions of I−III are determined kinetically, via the energy difference between TSe and TSf. Similarly, the same set of cycles I−III, or one cycle I, or even part of it are likely valid for other coordinatively saturated (pre)catalysts lacking N− 6651


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ACS Catalysis

one (X = N, C), but rather, its purpose was to attempt to understand the actual role of the ligand in the catalytic reaction with bifunctional catalysts. If there is the possibility to stabilize the determining transition states via X−H···O HBIs, these catalysts will always do so. The stronger that X−H···O HBIs are, the more that stabilization of determining transition states will be achieved, and the better that turnovers will be. Although this does not exclude that highly enantioselective catalysts lacking N−H functionalities relevant to outer-sphere reduction will be discovered in the future, an N−H functionality or functionalities in close proximity to the metal are apparently important in asymmetric reductions, in terms of orienting the substrate and making only two minimum energy Re- and Si-face transition states possible.37 Stabilization of the determining transition states via X−H···O HBIs accompanied by the behavior of the ligand as chemically innocent, expands the term “metal−ligand bifunctional molecular catalyst”, which to this point has relied almost exclusively on the cleavage/formation of X−H bonds, as currently seems to be the case only with Shvo-type catalysts.

outer-sphere from the coordinatively saturated catalyst complex, whereas the H+ moiety originates from an η2-H2-ligand generated in the subsequent step and/or by protic solvent. This H−/H+ mechanism is mechanistically similar to Bullock’s ionic hydrogenation,92 which conceptually is an H+/H− mechanism in which H+ originates from η2-H2-ligand of a cationic complex (e.g., ref 93)

3. CONCLUSIONS The elucidation of the mechanisms of catalytic reactions is a much more ambiguous task than is commonly accepted.94 This is a result of three main factors; (1) experimental problems in studies of catalytic cycles (short time-scales and sensitivities of physical methods used, inherently different conditions used in stoichiometric versus those in catalytic reactions, rough approximations38 used in commonly employed models of reaction kinetics such as transition state95 and RRKM96 theories, H/D scrambling,97 quantum tunneling effects,98 post-transition-state bifurcations27c on the PES27); (2) human factors; and (3) inevitable ambiguities in the interpretation of computational data.99 Indeed, computational quantum chemistry has become a powerful tool with which to investigate chemical reactions at the molecular level. The very complicated nature of even the simplest catalytic reactions, the absence of adequate computing resources, the use of oversimplified models, overuse of authoritative concepts, and strong convictions such as “the reaction must be concerted” gleaned from organic chemistry textbooks, separately or collectively represent downsides to the incorrect usage of modern computational chemistry. It often appears that it is not actually important to understand a reaction mechanism but instead to state that the mechanism is understood, computed, or confirmed by calculations. The field of metal−ligand bifunctional catalysis is flooded with computational studies that have already “established” a mechanism, and these findings have been replicated in multiple reviews entrenching an “accepted” mechanism, the core assumption of which is cleavage/formation of X−H bonds. The revised mechanism for the Noyori hydrogenation,34a Noyori−Ikariya transfer hydrogenation,34b and Morris asymmetric hydrogenation partially described in this work as well as established for Ru-MACHO-catalyzed ester hydrogenation,8,41 suggest that the ligand is involved in the catalytic reaction not via a reversible H+ transfer but rather via a stabilization of determining transition states via N−H···O hydrogen-bonding interactions. Most importantly, from a conceptual point of view, catalytic hydrogenation predominantly proceeds via a chemically innocent ligand through reduction of the CO functionality within the outer-sphere,42 and catalyst regeneration occurs via η2H2 and dihydrogen-bonded complexes. The chemical intactness of the ligand realized in these reactions is an important realization in further molecular catalyst design and here we primarily envision that alkylation of the N−H functionality may lead to beneficial turnover under certain conditions. At least four such examples of well-defined alkylated catalysts relevant to outersphere hydrogenation have been recently discovered.37,43 It appears that high turnover numbers and CO/CC chemoselectivities can indeed be achieved by alkylation of N−H functionality within M/NH Noyori-type catalysts. At least two examples of 18e− (pre)catalysts lacking N−H functionalities were reported to have appreciable to high turnover numbers.44b−d In summary, the purpose of this work was not to suggest immediately replacing an X−H functionality with an X−Alkyl

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b01791. Computational details, methodology, energy data, Cartesian coordinates for optimized structures, and other details (PDF) Frequency calculations for TSII−TSIV, TS1−TS5, and TS9−TS11 (ZIP)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Pavel A. Dub: 0000-0001-9750-6603 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Computations in this work were performed by using Darwin Computational Cluster at Los Alamos National Laboratory. The authors thank Josh Smith (C-DO, LANL) for the design of the Cover Picture.

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REFERENCES

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ACS Catalysis (78) (a) Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett. 1996, 77, 3865−3868. (b) Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett. 1997, 78, 1396−1396. (79) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241. (80) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (81) Peverati, R.; Truhlar, D. G. Phys. Chem. Chem. Phys. 2012, 14, 13171−13174. (82) (a) Perdew, J. P.; Schmidt, K. AIP Conf. Proc. 2000, 577, 1−20. (b) Car, R. Nat. Chem. 2016, 8, 820−821. (c) Medvedev, M. G.; Bushmarinov, I. S.; Sun, J.; Perdew, J. P.; Lyssenko, K. A. Science 2017, 355, 49−52. (83) Sandoval, C. A.; Ohkuma, T.; Muniz, K.; Noyori, R. J. Am. Chem. Soc. 2003, 125, 13490−13503. (84) Zimmer-De Iuliis, M.; Morris, R. H. J. Am. Chem. Soc. 2009, 131, 11263−11269. (85) We found that that outer-sphere hydride transfer with this catalyst, in contrast to the Noyori catalyst, proceeds via a conformation of the actual catalyst in which the five-membered TMEN ring adopts a symmetrical envelope configuration, despite the fact that the initial trans-dihydride complex possesses the most-stable delta configuration of the same ring. More details will be reported in a separate contribution, see ref 41. (86) Reactions (II) and (III) in Figure 13, in contrast to reaction (I) in Figure 11, involve different amount of species on the right side and left side of each reaction, respectively. Their thermodynamics should be compared on a free-energy scale; however, modern computational chemistry cannot typically handle properly enthropy for such cases 87, adding additional uncertainty to each numerical value of free energy. We do not believe, however, that the value of uncertainty is comparable with the 20 kcal·mol−1 energy difference between the transition states. (87) Dub, P. A.; Poli, R. J. Mol. Catal. A: Chem. 2010, 324, 89−96. (88) (a) Morris, S. A.; Gusev, D. G. Angew. Chem., Int. Ed. 2017, 56, 6228−6231. (b) Gusev, D. G. ACS Catal. 2016, 6, 6967−6981. (c) Vicent, C.; Gusev, D. G. ACS Catal. 2016, 6, 3301−3309. (d) Hasanayn, F.; Harb, H. Inorg. Chem. 2014, 53, 8334−8349. (e) Hasanayn, F.; Baroudi, A.; Bengali, A. A.; Goldman, A. S. Organometallics 2013, 32, 6969−6985. (f) Hasanayn, F.; Baroudi, A. Organometallics 2013, 32, 2493−2496. (89) There have been three more examples also recently reported, but at least one catalyst was suggested to operate via classical Schrock− Osborn (inner-sphere) mechanism, ref 90. (90) (a) Yuwen, J.; Chakraborty, S.; Brennessel, W. W.; Jones, W. D. ACS Catal. 2017, 7, 3735−3740. (b) Bellows, S. M.; Chakraborty, S.; Gary, J. B.; Jones, W. D.; Cundari, T. R. Inorg. Chem. 2017, 56, 5519− 5524. (c) Xu, R.; Chakraborty, S.; Yuan, H.; Jones, W. D. ACS Catal. 2015, 5, 6350−6354. (91) Kothandaraman, J.; Goeppert, A.; Czaun, M.; Olah, G. A.; Prakash, G. K. S. J. Am. Chem. Soc. 2016, 138, 778−781. (92) Bullock, R. M. Chem. - Eur. J. 2004, 10, 2366−2374. (93) Dobereiner, G. E.; Nova, A.; Schley, N. D.; Hazari, N.; Miller, S. J.; Eisenstein, O.; Crabtree, R. H. J. Am. Chem. Soc. 2011, 133, 7547−7562. (94) Gridnev, I.; Dub, P. A. Enantioselection in Asymmetric Catalysis; CRC Press LLC: Boca Raton, 2016. (95) (a) Wigner, E. Trans. Faraday Soc. 1938, 34, 29−41. (b) Eyring, H. J. Chem. Phys. 1935, 3, 107−115. (96) (a) Marcus, R. A. J. Chem. Phys. 1952, 20, 352−354. (b) Marcus, R. A. J. Chem. Phys. 1952, 20, 355−359. (c) Kassel, L. S. Chem. Rev. 1932, 10, 11−25. (d) Rice, O. K.; Ramsperger, H. C. J. Am. Chem. Soc. 1927, 49, 1617−1629. (97) Wu, X.; Liu, J.; Di Tommaso, D.; Iggo, J. A.; Catlow, C. R. A.; Bacsa, J.; Xiao, J. Chem. - Eur. J. 2008, 14, 7699−7715. (98) Bell, R. P. Chem. Soc. Rev. 1974, 3, 513−544. (99) This paper does not discuss issues of concern in computational studies of bifunctional catalysts such as accuracy in energy calculations (both uncertain and unexamined), possible other spin configurations, possible ligand hemilability and, as a result, the possibility of certain steps to proceed via an inner-sphere coordination.

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MetalâLigand Bifunctional Catalysis: The âAcceptedâ Mechanism, the

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