Intramolecular C–H Activation Reactions of Ru(NHC) Complexes

Combined with H2 Transfer to Alkenes: A Theoretical Elucidation of Mechanisms and Effects of Ligands on Reactivities

Katharina Marie Wenz,a Peng Liu,*a,b and K. N. Houk*a aDepartment of Chemistry and Biochemistry University of California, Los Angeles Los Angeles, CA 90095-1569 bDepartment of Chemistry University of Pittsburgh Pittsburgh, PA 15260

Contact: [email protected], [email protected]

Abstract Recent experimental studies have identified Ru(II) NHC complexes that are highly reactive in the tandem intramolecular C(sp3)–H activation of an N-alkyl substituent to form a metallacycle, and transfer hydrogenation of alkenes. These complexes are promising candidates for tandem catalytic processes that depend on a reversible uptake of hydrogen ('borrowing hydrogen catalysis'). We have elucidated the reaction mechanisms by density functional theory calculations and investigated ligand effects on reactivity. The reaction of ruthenium dihydride complex [Ru(H)2(NHC)(CO)(PPh3)2] (1) with ethylene occurs via dissociative ligand exchange to replace one of the phosphine ligands with ethylene, followed

1 by hydride migration and reductive elimination to form a Ru(0) intermediate. Subsequent C– H activation occurs via an oxidative addition mechanism. Bulkier NHC and phosphine ligands facilitate the dissociation of phosphine, which leads to a lower overall barrier. In addition, the N-iPr substituted NHC ligand promotes the C–H oxidative addition/ruthenacyclization due to the release of steric strain caused by the N-iPr group and the substituents on the NHC backbone.

The reaction with the monohydride monochloride complex [RuHCl(NHC)(PPh3)2] (2) occurs via ligand exchange and hydride migration to form an alkyl ruthenium(II) complex. The type of phosphine ligand determines whether the subsequent intramolecular C–H activation proceeds via an associative or a dissociative mechanism. In the associative pathway, C–H activation occurs via a concerted σ-bond metathesis mechanism, which directly transfers the hydrogen atom from the C–H bond of the N-alkyl group on the NHC to the alkyl ligand on ruthenium. In the dissociative pathway, C-H activation occurs via stepwise C-H oxidative addition to form a Ru(IV) intermediate followed by reductive elimination of the alkane product.

Introduction The low reactivity of C–H bonds makes selective C–H bond activation one of the major challenges in organic chemistry.1 Recent advances in C–H activations with Ir,2 Pd,1b,3 and Rh4 catalysts have led to many efficient C–H functionalization strategies. C–H activation reactions with ruthenium complexes are relatively less developed,5 although ruthenium catalysts have exhibited great reactivity and stability in many important catalytic processes such as olefin metathesis,6 hydrogenation,7 and transfer hydrogenation8 reactions. Interestingly, although only a few examples of Ru-mediated C(sp3)–H activation reactions have been reported,9,5g these processes may take place via several distinct mechanistic pathways (Figure 1) 10 including a two-step mechanism involving C–H oxidative addition followed by reductive elimination,11 σ-bond metathesis of an agostic complex (σ-complex assisted metathesis, or σ- CAM), 12 a base-induced electrophilic C–H activation, or a carboxylate-assisted concerted metalation-deprotonation (CMD) mechanism.5a,5b,13

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Figure 1. Mechanisms of Ru-mediated C–H activation generally start with the formation of an agostic precomplex. Concerted metalation-deprotonation (CMD) pathways assisted by a carboxylate ligand and an external base are shown in pink and blue, respectively. Stepwise oxidative addition and reductive elimination proceed via the green pathway. σ-Bond metathesis, or σ-complex assisted metathesis (σ-CAM), proceeds via a trapezoidal transition state (red pathway).

An interesting type of reactivity of Ru(NHC) complexes involves intramolecular C(sp3)–H activation reactions of the N-aryl or N-alkyl groups on the N-heterocyclic carbene (NHC) ligands to generate a five- or six-membered metallacycle complex. This process is one of the key decomposition pathways of ruthenium olefin metathesis catalysts.14 The Grubbs group recently revealed that the products of similar C–H activation reactions of Ru(NHC) complexes are highly Z-selective olefin metathesis catalysts.15 Mechanistic studies from the Grubbs and Houk groups indicated a carboxylate-assisted concerted metalation- deprotonation (CMD) mechanism for this C–H activation.16 Intriguing studies on intramolecular C–H activations of Ru(NHC) hydride complexes were reported by Whittlesey, Williams, and coworkers. 17 Alkenes react with dihydride complexes such as [Ru(H)2(NHC)(CO)(PPh3)2] (1), to form alkane and a metallacyclic product (1’) with a new Ru–C bond (Figure 2a). Upon hydrogenation or transfer hydrogenation with alcohol, the dihydride complex 1 is regenerated. The C–H activation reactivity is affected by 3 the N-alkyl groups on the NHC ligands. The N,N’-diisopropyl NHC (IiPr2Me2) in complex 1 is more reactive than the N,N’-diethyl ligand (IEt2Me2).17b Similar alkene hydrogenation reactions were later reported with ruthenium monohydride monochloride complex 2 (Figure 2b).18,19

Figure 2. a. Coupled alkene hydrogenation and intramolecular C–H activation of complex 1 (R=SiMe3). b. Coupled alkene hydrogenation and intramolecular C–H activation of complex 2 (R=H).17,18

The reversible C–H bond cleavage accompanying alkene hydrogenation offers great potential to incorporate such processes into more sophisticated tandem reactions. A well known example employing this strategy is the three-step cycle for alkane metathesis, which involves reversible alkane dehydrogenation by iridium catalysts, followed by Mo-catalyzed olefin metathesis and hydrogenation of olefin to yield new alkane molecules (Figure 3b).20 Similarly, the dehydrogenation/hydrogenation cycle with Ru(NHC) complexes has been incorporated into many catalytic processes, which are now called “borrowing hydrogen catalysis”.21 One such example employing the interconversion between 1 and 1’ is a tandem dehydrogenation/Wittig/hydrogenation reaction that allows for the formation of C–C bonds from alcohols (Figure 3a).17b Here, ruthenium complex 1 reacts with cyanoalkenes to form cyanoalkanes and metallacycle complex 1’, followed by transfer hydrogenation from an alcohol to regenerate complex 1 and form an aldehyde.

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Figure 3. Examples of tandem reactions based on reversible hydrogenation/dehydrogenation cycles. (a) Ru(NHC)-catalyzed tandem alcohol dehydrogenation, Wittig reaction and alkene hydrogenation; (b) alkane metathesis with an Ir/Mo dual catalysts system.

The Macgregor and Whittlesey groups performed computational studies on the intramolecular C–H activations of an Ru(NHC) complexes and explored the base-induced C– H activation pathway.22 A mechanistic study on ligand exchange processes and C-C and C-H oxidative addition with N-aryl substituted NHC ligands was also conducted23, as well as a comparative analysis of C-X (X =CH3, H, OH, OCH3, NH2, CF3, F) oxidative addition with these ligands 24 , though the latter study used an extremely simplified model system. The mechanism of alkene-promoted C–H activation reactions shown in Figure 2 has not been investigated computationally. In this study we report the mechanisms of the tandem alkene hydrogenation/intramolecular C–H activation reactions of 1 and 2 using the full experimental system. Through our mechanistic investigations we show, that the dihydride Ru(II) complex 1 and the hydride chloride Ru(II) complex 2 react in a different manner. Complex 1 reacts through a dissociative process, with stepwise hydride migration, reductive elimination and oxidative addition via a Ru(0) intermediate, as proposed in the original experimental paper by the Whittlesey group17b. To the best of our knowledge, C(sp3)-H activation by a Ru(0) complex has only been reported using low-valent [Ru3(CO)12] complexes by Kakiuchi5g and others25. In contrast, the C-H activation reaction of 2 can either proceed through a reactive Ru(IV) intermediate or a concerted σ-bond metathesis process, depending on whether a dissociative or associative mechanism takes place. Such diversity in

5 mechanistic behavior has previously only been reported in computational studies by

Eisenstein et al on the C-H activation of methane by [Tp(PH3)Ru(CH3)(η2-H-R)] (R=H,CH3; Tp=hydridotris(3,5-dimethylpyrazolyl)borate). 26 ,13f The origins of NHC and phosphine ligand effects on the activity of the Ru catalyst in C–H activation reactions are not fully understood, although electronic effects on the strength of the agostic precomplex have been investigated by Sabo-Etienne et al. using Natural Bond Orbital (NBO) analysis 27 and the influence of anionic ligands on methane C-H activation via σ-bond metathesis with

[TpRu(CO)X] (X=CH3, OH, OMe, NH2, and NMe2) complexes has been studied by Gunnoe et al.12c Our computational studies provide a detailed understanding of the electronic and steric effects that determine the mechanisms and reactivity of (NHC) Ru(0) and Ru(II) complexes in coupled intramolecular C(sp3)–H activation and alkene hydrogenation reactions. This opens the pathway for the rational design of tandem ruthenium based catalysts employing C(sp3)-H activation reactions.

Computational Methods All calculations were performed using Gaussian09. 28 Geometry optimizations, vibrational frequency and intrinsic reaction coordinate (IRC) calculations were carried out with B3LYP and a mixed basis set of SDD for Ru and 6-31G(d) for other atoms. A comparison of select geometrical parameters of the optimized geometry of the full experimental system

1(IiPr2Me2/PPh3) with the crystal structure values is given in Table S1 in the Supporting Information. Deviations in computed bond lengths and angles from those in the crystal structure are generally small, around 0.02 Å and 2° respectively. Deviations in the Ru–P distances are greater, about 0.08 Å. To obtain more reliable values for electronic energies, single point energy calculations using M06/6-311+G(d,p)–SDD(Ru) and SMD solvation corrections for benzene were performed. Based on previous benchmark studies on related ruthenium complexes,29 this level of theory is expected to provide reasonable energetics in the present study, including the dissociation energies of the phosphine ligand and the alkene binding energies of the Ru(NHC) complexes.

6 Results and Discussion Mechanism of the C–H activation/transfer hydrogenation reaction with complex 1 We performed DFT calculations to study the possible mechanisms of the reactions of 1 and 2 with ethylene to form ruthenacycles 1’ and 2’, respectively, plus ethane (Figure 2). The octahedral complexes 1 and 1’ are 18 electron species, while the five-coordinated 2 and 2’ are 16 electron species. Calculations were initially performed on model system

1(IiPr2Me2/PMe3), with PMe3 instead of PPh3 ligands and ethylene as a substrate to determine the most likely mechanistic pathways (Figure 4). It became apparent though, that the choice of phosphine ligand influences significantly the barrier heights of all major steps of the reaction. (For full reaction energy profile with the smaller model system

1(IiPr2Me2/PMe3), see SI.) The mechanism of the reaction is heavily dependent on the ability of the complex to associate and dissociate the phosphine ligands, since the hydride migration step can only take place after one of the phosphine ligands dissociates. The mechanism also depends on the association of the alkene substrate and the elimination of the reduced reaction product. As a result, the use of smaller model complexes only provided a rough guide to the most feasible reaction pathways and coordination geometries. Subsequently, the reaction mechanisms of the experimentally used ruthenium complexes 1(IiPr2Me2/PPh3) and 1(IEt2Me2/PPh3) with ethylene and TMS-CH=CH2, and 2(IiPr2Me2/PPh3) with ethylene were studied in the computations. The influence of the N-alkyl substituents on the NHC ligand and the effect of a bulkier and more electron-rich alkene on the reaction profile will be discussed later in this paper.

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Figure 4. Structure of model complexes 1(IiPr2Me2/PMe3) and 2(IEt2H2/PMe3), and experimental complexes

1(IiPr2Me2/PPh3), 1(IEt2Me2/PPh3) and 2(IiPr2Me2/PPh3).

Figure 5 shows the computed energy profile for the reaction of 1(IiPr2Me2/PPh3) and ethylene to form 1(IiPr2Me2/PPh3)’ and ethane. The DFT calculations indicate that the reaction of 1(IiPr2Me2/PPh3) and ethylene to form 1(IiPr2Me2/PPh3)’ and ethane proceeds through a mechanism with four basic steps shown in Figure 5: (1) dissociative ligand exchange of a phosphine ligand by ethylene, (2) ethylene migratory insertion (hydride migration), (3) reductive elimination of ethane, and (4) oxidative addition of a primary C–H bond of the N-isopropyl group on the NHC ligand to give the ruthenacycle product

1(IiPr2Me2/PPh3)’. Re-coordination of the second phosphine ligand may occur either before or after the reductive elimination/oxidative addition steps. The octahedral complex, 1 (∆G = 0.0 kcal/mol) is coordinatively saturated, and ligand exchange to replace one of the PPh3 ligands with ethylene is expected to occur through a dissociative pathway via 3 to form 4, which is 6.7 kcal/mol less stable than 1. The most favorable geometry for complex 1 features a trans phosphine arrangement with the two hydride ligands cis to each other. The intermediate 3 is stabilized by an agostic interaction with one of the N-isopropyl groups. The coordination geometry of complex 1 was confirmed by 31P-NMR studies in the Whittlesey group.17b By monitoring the exchange reaction of PPh3 for P(p-Tol)3 they showed, that phosphine dissociation occurs rapidly at room temperature which agrees with the very low computed phosphine dissociation energy of 1. One of the hydride ligands in 4 migrates to ethylene to give the five-coordinated 16- electron intermediate 6. C-H reductive elimination from the intermediate 6 to form an agostic Ru(0) intermediate 8 and ethane (7-TS, G‡=13.7 kcalmol-1) requires a barrier similar to that for hydride migration. Phosphine ligand association occurs after the reductive elimination step to form a more stable four-coordinate Ru(0) complex 13. This also stabilizes the subsequent oxidative addition transition state in the associative pathway (shown in blue in Figure 5) relative to the dissociative pathway (shown in red) in which ligand association occurs after oxidative addition. The oxidative addition to the C–H bond of the N-isopropyl group is rate-determining and requires a barrier of 14.6 kcal/mol (1314-TS) to form the ruthenacycle product 1(IiPr2Me2/PPh3)’. The product complex with a cis phosphine 8 arrangement is about 6.5 kcal mol-1 more stable than the isomeric complex 17 with a trans phosphine arrangement (purple pathway in Figure 5). This is in agreement with the crystal structure of 1(IiPr2Me2/PPh3)’ published by the Whittlesey group which has a cis arrangement of the PPh3 ligands. The optimized structures of the transition states in the preferred reaction pathway are shown in Figure 6. The transition states for the less favorable pathways are shown in the SI.

Figure 5. M06/6-311+G(d,p)-SDD Gibbs free energy profile for the ethylene hydrogenation and ruthenacyclization of 1(IiPr2Me2/PPh3). The reductive elimination occurs via the dissociative mechanism (7- TS) with one triphenylphosphine ligand bound to the ruthenium. Association of a second phosphine ligand after the reductive elimination renders the oxidative addition step via 14-TS more favorable (blue pathway). Enthalpy values are shown in parentheses.

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Figure 6. Optimized structures of a. hydride migration TS (5-TS), b. reductive elimination TS (7-TS) c. oxidative addition TS (14-TS) with 1(IiPr2Me2/PPh3). Bond lengths are given in Å.

We computed other possible pathways using a model system with a smaller NHC ligand 1(IEt2H2/PMe3), including σ-bond metathesis of the N-Et C–H bond in 3 to give the metallacycle and η2-bound H2. Our calculations indicate that this path requires a much higher activation barrier of 45.3 kcalmol-1. The details are given in the SI.

Effects of Substrate on Reactivity We explored the effect of the TMS-substituted alkene used in experimental studies by the Whittlesey group on the reaction mechanism, compared to ethylene. The energy profile for the reaction of 1(IiPr2Me2/PPh3) with TMS-CH=CH2 is shown in Figure 7, and the transition state structures of the hydride migration and reductive elimination TS are shown in Figure 8.

The dissociative ligand exchange to replace a phosphine ligand by a TMS-CH=CH2 is endergonic by 12.0 kcal mol-1, which is 5.3 kcal mol-1 less favorable compared to the corresponding ligand exchange with ethylene. The alkene coordination in 18 is destabilized by the steric hindrance between the TMS-group and the phosphine coordinated trans to the

10 NHC ligand. Hydride migration is the rate-determining step, with an activation barrier of 17.2 kcal mol-1 (19-TS).30

Figure 7. M06/6-311+G(d,p)-SDD Gibbs free energy profile for the hydrogenation of TMS-CH=CH2 and ruthenacyclization of 1(IiPr2Me2/PPh3). Only the more favorable, dissociative pathway is shown for hydride migration and reductive elimination steps. Association of a second phosphine ligand takes place after the reductive elimination (blue pathway). Enthalpy values are shown in parentheses.

The barrier for the hydride migration step is significantly influenced by the alkene substrate. The TMS-substituted alkene is more electron-rich than ethylene, and we expected the activation barriers for hydride addition to the C=C double bond to be lower. We find instead, that because the high steric demand of the TMS group and the bulky phosphine ligands on the complex make coordination of the alkene more difficult, the overall activation barrier for hydride migration is increased, and the reactivity is lower than that in the reaction with ethylene. The reductive elimination step is less sensitive to the alkene substituent that

11 is β to the metal and the barrier for reductive elimination is less affected (7-TS versus 21- TS).

Figure 8. Optimized structures of a. hydride migration TS (19-TS), b. reductive elimination TS (21-TS) with

1(IiPr2Me2/PPh3) and TMS-CH=CH2. Bond lengths are given in Å.

Effects of NHC and Phosphine Ligands on Reactivity Experiments from the Whittlesey group indicated, that bulky N-alkyl groups and methyl substituents on the backbone of the NHC ligand increase the reactivity toward the C–H activation of Ru(NHC) hydride complexes. The IiPr2Me2-ligated complex 1(IiPr2Me2/PPh3)’ discussed before is the most active catalyst for the aforementioned tandem Wittig/transfer hydrogenation reaction.17b The IEt2Me2-ligated complex 1(IEt2Me2/PPh3) and the IiPr2H2- ligated complex 1(IiPr2H2/PPh3) showed a reduced activity towards the tandem hydrogenation/C-H activation reaction: only 15 % conversion were reported in the catalytic reduction of TMS-CH=CH2 at 50 °C using 1(IEt2Me2/PPh3), and 8 % conversion using

1(IiPr2H2/PPh3), as opposed to 45 % conversion reported with 1(IiPr2Me2/PPh3)’ under the same conditions17b Similarly, the bulky iPr group on the NHC ligand also promotes the reaction of the monohydride monochloride complex 2 with ethylene (Figure 2b).18 To elucidate the origins of the effects of NHC ligand on reactivity, we computed the energy profile of the reaction of 1(IEt2Me2/PPh3) with TMS-CH=CH2. Both the dissociative and

12 associative pathways were computed (Figure 9). The optimized structures of the most favorable transition states in this reaction are shown in the SI.

Figure 9. M06/6-311+G(d,p)-SDD Gibbs free energy profile for the hydrogenation of TMS-CH=CH2 and ruthenacyclization of 1(IEt2Me2/PPh3). Only the more favorable, dissociative pathway is shown for hydride migration and reductive elimination steps. Association of a second phosphine ligand takes place after the reductive elimination (blue pathway). The product then isomerizes to give the complex with trans phosphine arrangement (purple structure). Enthalpy values are shown in parentheses.

The use of a less sterically hindered ligand (IEt2Me2) leads to a higher overall barrier of the reaction. The decrease of reactivity is mostly due to the stabilization of the bisphosphine reactant relative to the following TSs and reaction intermediates. This is apparent in the increased phosphine dissociation energy (12.1 kcal mol-1 for

1(IEt2Me2/PPh3) compared to 7.9 kcal mol-1 for 1(IiPr2Me2/PPh3)). The barriers for reductive elimination and oxidative addition steps are also much increased with 1(IEt2Me2/PPh3), as compared to the IiPr2Me2-NHC ligated complex. The 13 reductive elimination step (26-TS) proceeds with an activation barrier of 20.4 kcal mol-1, 5 kcal mol-1 higher than with the IiPr2Me2 ligand. This makes reductive elimination the rate- determining step for the reaction with 1(IEt2Me2/PPh3). With the IiPr2Me2 ligand, the iPr groups are forced into a rigid conformation by the methyl groups on the NHC backbone. This facilitates the reductive elimination and dissociation of the reduced alkene to form an Ru(0) complex. With the smaller IEt2Me2 ligand, the Ru(II) center in intermediate 25 is less sterically congested, resulting in a higher barrier of reductive elimination.

Similar to the reaction with the IiPr2Me2 ligand, the intramolecular C-H oxidative addition also takes place after the reassociation of a PPh3 ligand (31-TS). The activation barrier for oxidative addition is raised by 3.3 kcal mol-1 in comparison to the IiPr2Me2 ligand to give a barrier of 17.9 kcal mol-1 (31-TS). The increased reactivity of the N-iPr substituted ligand in oxidative addition is mainly due to steric effects. With the IiPr2Me2 ligand, the optimized geometries of the intermediate before oxidative addition (13) indicated unfavorable steric repulsions between the N-iPr groups and the methyl groups on the NHC backbone. These steric clashes are diminished in the oxidative addition transition states, where the N-iPr group is rotated towards the metal to form the ruthenacycle product (Table 1, entry 1). The distances between N-iPr and Me, between the two backbone Me groups, and between Me and N’-iPr are only 2.15, 2.10, and 2.12 Å, respectively. All three distances increase noticeably in the oxidative addition transition state 14-TS, to 2.20, 2.15, and 2.17 Å, respectively. In contrast, there are no steric clashes with the N-Et group in intermediate 30 (Table 1, entry 2). In previous studies, the reactivity of base-induced C–H activation was attributed to the acidity of the C–H bond. 9b Here, the effects of acidity is expected to be small in the C-H oxidative addition process. Our analysis of atomic charges shows only small changes in electron density in the oxidative addition step (see SI for details).

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Table 1. Release of unfavorable steric interactions between N,N’-iPr (R1/R4) and the NHC backbone methyl groups (R2/R3) in the oxidative addition step. The shortest H–H distances between these groups, d(R1-R2), d(R2- R3), and d(R3-R4),are given in Å. Gibbs free energy barriers (G‡) are in kcal mol–1 and are with respect to intermediate A.

NHC intermediate (A) oxidative addition TS entry R1/R4 R2/R3 G‡ ligand d(R1-R2) d(R2-R3) d(R3-R4) d(R1-R2) d(R2-R3) d(R3-R4)

1 IEt2Me2 Et Me 2.21 2.22 2.30 2.48 2.23 2.23 17.9

2 IiPr2Me2 iPr Me 2.15 2.10 2.12 2.20 2.15 2.17 14.6

The crystal structure of the product complex 1(IEt2Me2/PPh3)’ published by the Whittlesey group shows a trans phosphine arrangement, and our calculations also indicate that in this case the trans phosphine product is about 1.1 kcal mol-1 more stable than the cis phosphine product. This is rather surprising since with 1(IiPr2Me2/PPh3)' as discussed beforehand the cis phosphine product is formed selectively. This leads to the conclusion that a trans arrangement of phosphine ligands is electronically more favorable, but this is counteracted in the 1(IiPr2Me2/PPh3)' complex by the steric interactions between the N-iPr substituents on the NHC ligand and the bulky PPh3 ligands. Interestingly the oxidative addition transition state with trans phosphine arrangement is much higher in energy than the TS with cis phosphine arrangement discussed above. This does not have an impact on the product complex observed experimentally, since the phosphine dissociation barriers are very low (7.8 and 14.3 kcal mol-1 from the trans phosphine and cis phosphine isomers of

1(IiPr2Me2/PPh3)', respectively).

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Mechanism of the C–H activation/transfer hydrogenation reaction with complex 2 As shown in Figure 1, the ruthenium(II) monohydride monochloride complex 2 reacts with alkenes in a very similar fashion as the ruthenium(II) dihydride complex 1 discussed previously. However, when replacing one of the hydride ligands with chloride, the C–H reductive elimination following hydride migration is no longer feasible. This indicates a different mechanism for the reaction with complex 2. As with 1 we first elucidated possible reaction pathways using a smaller model system

2(IEt2H2/PMe3). The three computed mechanisms, dissociative, associative, and -bond metathesis with this model system can be found in the SI. Based on the calculations with the model system, the dissociative and associative pathways are the most likely reaction pathways and were thus studied with the full experimental system. The -bond metathesis pathway, in which the C–H activation precedes hydride migration to the alkene, is very unfavorable with an activation barrier of 47.3 kcal mol-1, and this was not calculated with the experimental system (see SI for more details). The energy profiles for the associative and dissociative pathways with the experimental system 2(IiPr2Me2/PPh3) are shown in Figure 10. The key transition state structures in these pathways are shown in Figure 11. 2(IiPr2Me2/PPh3) was observed experimentally to be present in three isomeric forms in dichloromethane solution: the non- agostic trans-phosphine complex, and two agostic complexes, with trans

(2(IiPr2Me2/PPh3)_a) and cis phosphine arrangement (2(IiPr2Me2/PPh3)_b), respectively.18 These were found computationally to be close in terms of free energy and enthalpy, which accounts for all three complexes to be observable at room temperature

(Table 2). The stabilization by agostic interaction in 2(IiPr2Me2/PPh3)_a and b does seem to be overcompensated by the rise in steric interaction between the backbone methyl and isopropyl substituents, and also the loss in entropy.

16 Table 2. Computed relative energies of isomers of 2(IiPr2Me2/PPh3) observed in solution.18

i i 2(I Pr2Me2/PPh3) 2(IiPr2Me2/PPh3)_a 2(I Pr2Me2/PPh3)_b ΔG 0.0 4.3 5.2

(ΔH) (0.0) (1.4) (2.9)

kcal mol-1

Figure 10. M06/6-311+G(d,p)–SDD Gibbs free energy profile for ethylene hydrogenation and ruthenacyclization of 2(IiPr2Me2/PPh3). The associative mechanism (blue) proceeds via a rate-determining - 17 bond metathesis step (37-TS). The more favorable dissociative pathway (red) proceeds via consecutive oxidative addition (42-TS) and reductive elimination (44-TS). Free energy profile for a higher energy -bond metathesis mechanism is included in the Supplementary Information. Enthalpy values are shown in parentheses.

Figure 11. Computed transition states in the associative and dissociative mechanistic pathways in the reaction of 2(IiPr2Me2/PPh3). a. Dissociative hydride migration TS (40-TS). b. Oxidative addition TS (42-TS). c. Reductive elimination TS (44-TS). d. Associative hydride migration TS (35-TS) e. Associative-Bond metathesis TS (37-TS). Bond lengths are given in Å.

It is apparent in the energy profile, that C-H activation can either take place via stepwise oxidative addition and reductive elimination or a concerted σ-bond metathesis step, which directly transfers the hydride from the NHC alkyl substituent to the alkyl group on

18 ruthenium. In this case, this selectivity is dependent on whether an associative mechanism

(blue, with two PPh3 ligands bound to the ruthenium) or dissociative mechanism (red, with one PPh3 ligand bound to the ruthenium) takes place. In the associative (blue) pathway, association of ethylene and hydride migration from the ruthenium alkene complex (34) lead to an alkyl ruthenium chloride intermediate (36), which undergoes C–H activation of the N- Et group via σ-bond metathesis to form ethane and the ruthenacycle product

2(IiPr2Me2/PPh3)’. The σ-bond metathesis that activates the N-Et C–H bond and eliminates an ethane is the rate-determining step in this associative pathway. The relatively high overall barrier (G‡ = 33.0 kcal mol-1, 37-TS) is in part due to the unfavorable association of an ethylene molecule in the associative pathway. Although complex 2(IiPr2Me2/PPh3) is coordinatively unsaturated, association of an ethylene molecule to form 34 is endergonic by 12.7 kcal mol-1. The more favorable dissociative pathway for this reaction is shown in red in Figure

10. The ligand exchange to replace one PPh3 with an ethylene to form intermediate 39 takes place via an associative pathway involving the 18-electron complex 34. The phosphine dissociation from 34 to form 39 is exergonic by 8.7 kcal mol-1. Similarly, the subsequent hydride migration (G‡ = 13.9 kcal mol-1, 40-TS) is also more favorable with only one phosphine bound to the metal center. Unexpectedly, neither 39 nor the alkyl ruthenium chloride intermediate 41 show an agostic interaction, as the agostic stabilization through coordination of a methyl C-H bond of the NHC ligand is counteracted by steric interactions and the associated loss of entropy. After formation of intermediate 41, the C–H activation proceeds through an oxidative addition transition state (42-TS) to form a six-coordinated Ru(IV) intermediate (43). Reductive elimination of ethane (44-TS) then leads to the ruthenacycle product. A σ-bond metathesis TS similar to 42-TS could not be located for this dissociative pathway. Since the oxidative addition intermediate 43 does not have a free coordination site, the corresponding bisphosphine complex is not formed.

In the C-H activation by Ru(II) a base-assisted mechanism is often invoked. Since PPh3 could be available as a base in the dissociative pathway shown in Figure 10, we also investigated the base-assisted metalation-deprotonation of intermediate 41 using PPh3. Our calculations showed that this pathway is very unfavorable with a computed barrier of ΔG‡ = 60.6 kcal mol- 1 (see details in the SI). The low reactivity of this deprotonation pathway is due to the

19 relatively low basicity of PPh3 in benzene. Previous literature reports indicate carboxylates or strong bases, such as IiPr2Me2, KOtBu, or KN(SiMe3)2, are usually required for the base- promoted deprotonation mechanism.22,5a,5b,13 We also calculated the reaction mechanism using the smaller model system

2(IEt2H2/PMe3). The basic mechanistic steps for the associative and dissociative pathways are very similar to those discussed above for the experimental system; however, now the associative pathway is much more favorable than the dissociative pathway. This is mostly due to the greatly reduced steric hindrance caused by the smaller phosphine ligands (PMe3 instead of PPh3) and the smaller NHC ligand. Details can be found in the SI.

Conclusion The mechanisms of alkene hydrogenation and intramolecular C(sp3)–H activation reaction of Ru-complexes 1 and 2 have been investigated with density functional theory. The C–H activation of complex 1 occurs via ligand exchange of a phosphine for ethylene, hydride migration, reductive elimination, and oxidative addition steps. The C–H oxidative addition step is rate-determining in the reaction of the experimental ruthenium complex 1(IiPr2Me2/PPh3) with ethylene. NHC ligands with bulkier N-alkyl groups favor the overall reaction by promoting phosphine dissociation and, after the reductive elimination step, the product dissociation from the metal complex. Bulkier NHC ligands also lead to lower barriers in the C–H oxidative addition (cyclometallation) step, which is accelerated by the additional steric strain caused by the N-alkyl groups and the NHC backbone substituents. The reaction with complex 2 proceeds via a different mechanism, which involves association of ethylene, hydride migration, and intramolecular C-H oxidative addition to form a Ru(IV) intermediate and reductive elimination of ethane. The reductive elimination step is rate-determining. With the smaller PMe3 in place of PPh3, the associative pathway is favored. Instead of the stepwise C-H oxidative addition/reductive elimination mechanism, a rate- determining σ-bond metathesis step directly transfers a hydrogen atom from the C–H bond of the N-alkyl group to the alkyl ligand attached to Ru to form the ruthenacycle product and the alkane. The origin of the different mechanisms between 1 and 2 is due to the ability of the dihydride complex 1 to form a Ru(0) intermediate via reductive elimination of alkane, while

20 in the case of the monohydride monochloride complex 2, formation of such Ru(0) complex is not possible. We have shown that the efficiency of hydrogen borrowing strategies with Ru NHC dihydride complexes such as 1 or Ru NHC monohydride monochloride complexes, such as 2, is dependent on a subtle interplay between steric demand of the NHC ligand, and steric demands and electron-donating ability of the phosphine ligands. The first can promote intramolecular oxidative addition reactions, as well as facilitate release of the product, while the latter determines whether associative or dissociative pathways are favored.

Supporting Information: Complete reference of Gaussian09, comparison of the crystal structure and B3LYP-optimized geometry of 1(IiPr2Me2/PPh3)’, computed transition state structures in the less favorable pathways in the reaction of 1(IiPr2Me2/PPh3) with ethylene, and in the reaction of

1(IEt2Me2/PPh3) with TMS-CH=CH2, Gibbs free energy profile and optimized TS structures in the reaction of 1(IiPr2Me2/PMe3), 1(IEt2H2/PMe3) and 2(IEt2H2/PMe3) with ethylene, natural population analysis of oxidative addition educts, TS, and products with

1(IEt2Me2/PPh3) and 1(IiPr2Me2/PPh3), discussion of an alternative reaction pathway involving σ-bond metathesis from 58 and an alternative σ-bond metathesis pathway in the reaction of 2(IEt2H2/PMe3) and a concerted metalation-deprotonation pathway from 41, XYZ Coordinates of all intermediates and transition states.

Acknowledgements The authors declare no competing financial interests. We are grateful for financial support from the Maersk Oil Research and Technology Center, Doha, Qatar, NSF (CHE-1361104 for K.N.H. and CHE-1654122 for P.L.), and a PROMOS fellowship from Albert-Ludwigs- Universität Freiburg and the DAAD to K.M.W. Calculations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF(ACI-1053575).

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30 The barrier for hydride migration to the β-position to the TMS group is only about 0.8

kcal mol-1 higher than for hydride migration alpha to the TMS group (19-TS). The

secondary alkyl ruthenium complex resulting from this step with the TMS group at the ɑ

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secondary alkyl ruthenium isomer to the branched silane product is disfavored due to

similar steric effects.

27