Benzoate Cyclometalation Enables Oxidative Addition of Haloarenes at a Ru(II) Center

The first Ru(II)-catalyzed arylation of substrates without a directing group was recently developed. Remarkably, this process only worked in the presence of a benzoate additive, found to be crucial for the oxidative addition step at Ru(II). However, the exact mode of action of the benzoate was unknown. Herein, we disclose a mechanistic study that elucidates the key role of the benzoate salt in the C–H arylation of fluoroarenes with aryl halides. Through a combination of rationally designed stoichiometric experiments and DFT studies, we demonstrate that the aryl–Ru(II) species arising from initial C–H activation of the fluoroarene undergoes cyclometalation with the benzoate to generate an anionic Ru(II) intermediate. The enhanced lability of this intermediate, coupled with the electron-rich anionic Ru(II) metal center renders the oxidative addition of the aryl halide accessible. The role of an additional (NMe4)OC(CF3)3 additive in facilitating the overall arylation process is also shown to be linked to a shift in the C–H pre-equilibrium associated with benzoate cyclometalation.


INTRODUCTION
The polyfluorobiphenyl unit is a recurrent building block found as a structural component in drugs, 1a−c agrochemicals, 1e,f and numerous functional materials 1g−m such as organic light-emitting diodes (OLEDs) 1j and liquid crystals. 1k,i Although cross-coupling methods can be applied to access these biaryl moieties, 2 C−H arylation strategies have been acknowledged as a more sustainable alternative strategy to selectively form aryl−aryl bonds. 3 In this context, fluorinated biaryls can be generated under Pd catalysis employing fluoroarenes with coupling partners such as aryl (pseudo)halides, 4a−d aryl boronic donors, 4e or simple arenes. 4f,g Alternatively, Cu-5 or Au-catalysts 6 can be used to promote analogous transformations. Recently, our group expanded upon the range of transition metal catalysts able to promote this particular type of coupling. 7 The arylation of fluoroarenes with aryl halides occurred with a Ru(II) catalyst, [Ru(t-BuCN) 6 ][BF 4 ] 2 , aided by (NMe 4 )OPiv and (NMe 4 )(4-F-C 6 H 4 CO 2 ) cocatalysts and (NMe 4 )OC(CF 3 ) 3 base in t-BuCN (Scheme 1a). Notably, this methodology is the first Rucatalyzed C−H arylation process operating without the need for a directing group in the arene.
Crucially, this Ru-catalyzed C−H arylation only proceeded when a benzoate salt was present, with all other bases and carboxylates tested unable to switch on the reaction. Indeed, when the arylation of polyfluoroarene 1a was carried out with bromobenzene 2a under optimized reaction conditions in the absence of the benzoate additive, no cross-coupled product 3aa was formed. To further clarify the surprising role of the benzoate source, a stoichiometric arylation between the catalytically active intermediate tetrafluorophenyl−Ru(II) complex Ru1b and 5-bromo-m-xylene 2b was performed (Scheme 1b). Biaryls 3bb and 3bb′ were formed only when the benzoate was added. Remarkably, the structurally related pivalate salt did not promote the transformation. These empirical results, along with mechanistic studies and DFT calculations, led us to suggest a catalytic cycle where, although the initial C−H activation of the fluoroarene is assisted by pivalate, the formal oxidative addition of the aryl halide could only proceed when benzoate was present. 7 However, the mechanism by which benzoate may facilitate oxidative addition remained unknown.
Herein, we report mechanistic studies elucidating the role of the benzoate salt. Our experiments demonstrate that aryl− Ru(II) species such as Ru1b, which are inert toward oxidative addition with aryl bromides 2, can undergo cyclometalation with the benzoate salt to form an anionic Ru(II) intermediate that is highly reactive toward oxidative addition and is essential to the reactivity of the system. In a similar vein, we have also recently proposed that the mechanism of the Ru(II)-catalyzed C−H arylation of N-chelating substrates with aryl (pseudo)halides involves a bis-cyclometalated Ru(II) species as the key intermediate required for oxidative addition to occur. 8

RESULTS AND DISCUSSION
2.1. Mechanistic Hypothesis for the Role of the Benzoate. The specific requirement for a benzoate salt for the reaction to proceed led us to hypothesize that the benzoate may be undergoing ortho-C−H activation as its mode of action. Scheme 2 outlines our proposed catalytic cycle for the process. After the initial C−H activation of the fluoroarene 1 to form the cationic fluoroaryl−Ru(II) complex II, a second C−H activation event on the benzoate would generate anionic Ru(II)-species IV featuring a cyclometalated benzoate unit. This more electron-rich Ru(II) intermediate IV would be more reactive toward oxidative addition with the aryl halide (to V) than the cationic complex II or the neutral species III. Reductive elimination from V would then produce the biaryl product. In contrast, an aliphatic carboxylate such as pivalate would be unable to undergo cyclometalation and thus would be unable to promote the desired arylation reaction. Indeed, whereas the cyclometalation of aromatic benzoates by Ru(II) complexes is well-known and recognized, 9,10 the more challenging β-cyclometalation of aliphatic carboxylic acids has yet to be observed.
2.2. Kinetic and Isotopic Studies. With this mechanistic framework in mind and given the possibility of isolating cationic intermediate II, we decided to examine stoichiometric arylation reactions to directly probe the cyclometalation and the oxidative addition steps without interference from the initial C−H activation of the fluoroarene (from I to II, Scheme 2). Thus, we started investigating the kinetic profile of the coupling of pentafluorophenyl−Ru(II) species Ru1c with bromoarene 2b in the presence of a variety of benzoate derivatives ( Figure 1). In order to standardize the measurements, Ru1c was preincubated for 20 min at 90°C with the benzoate salt prior to the addition of 2b. In agreement with our hypothesis, 2,6-disubstituted benzoate sources, which cannot undergo ortho-C−H activation, did not give any biaryl 3cb irrespective of the electronic effect of these groups (Me, F, OMe). Instead, paralleling our previous observations, (NMe 4 )-(C 6 H 5 CO 2 ) triggered the desired coupling. In view of the often reversible nature of the C−H activation in Ru(II) catalysis, 11 we predicted that the addition of an external base would shift the equilibrium III−IV toward IV (Scheme 2), thus enhancing the reactivity. Indeed, when (NMe 4 )-(C 6 H 5 CO 2 ) was used in combination with the base (NMe 4 )-OC(CF 3 ) 3 , a conspicuous acceleration of the rate of arylation was obtained. 12 These data strongly suggest that the proposed ortho-metalation to generate intermediate IV is a key step en route to the formation of the aryl−aryl bond.
In order to test this hypothesis further, catalytic arylation of nonvolatile polyfluoroarene 1a with bromoarene 2b was carried out utilizing the deuterated (NMe 4 )(C 6 D 5 CO 2 ) under standard optimized reaction conditions 7 (Scheme 3). Figure 1. Stoichiometric arylation of Ru1c with 2b employing (NMe 4 )-2,6-disubstituted benzoates or simple benzoate in the presence or in the absence of (NMe 4 )OC(CF 3 ) 3 base. Yield determined by GC-FID using hexadecane as internal standard.

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Article Analysis of the reaction mixture after 15 min revealed the formation of biaryl 3ab in 16% yield. More importantly, recovered fluoroarene 1a showed 14% deuteration, and recovered benzoic acid revealed a 41% H enrichment at the ortho positions. Since the only source of D was the benzoate salt, this experiment highlights the reversible nature of the steps from intermediate I to IV of the catalytic cycle (Scheme 2) and provides further evidence for the cyclometalation of the benzoic acid. Unfortunately, all attempts at isolation or in situ detection of IV starting from Ru1c in the presence of benzoate salts were unsuccessful, and this likely reflects the high energy of intermediate IV (see SI, section 5 for details and DFT studies below).
Subsequently, we set out to investigate whether a KIE was associated with the benzoate cyclometalation step. The initial arylation rates of two independent stoichiometric couplings of pentafluorophenyl-containing Ru1c (intermediate II in Scheme 2) with 5-bromo-m-xylene 2b using either (NMe 4 )-(C 6 H 5 CO 2 ) or (NMe 4 )(C 6 D 5 CO 2 ) were therefore recorded ( Figure 2). The rate of formation of biaryl 3cb with the benzoate source was 1.36 times faster than the one with the perdeuterated benzoic salt, suggesting that the cyclometalation of the benzoate (III to IV in Scheme 2) is kinetically relevant and likely an equilibrium under the reaction conditions. 13 2.3. Hammett and JafféPlots. In order to gain further mechanistic insights into the cyclometalation step of the benzoate additive, we compared the initial rates of formation of biaryl 3cb in the stoichiometric arylation reactions of Ru1c with 2b in the presence of a variety of electronically diverse 4substituted benzoate salts (Table 1). 14 First, and surprisingly, the rate of arylation (k obs ) increased with both electron-rich and electron-poor benzoates, with the parent unsubstituted benzoate displaying the slowest rate. A second observation from these data can be extracted from the corresponding Hammett plots (Figure 3). 15 Since both meta and para positions to the substituent are potentially involved in the process, we plotted log(k X /k H ) versus both σ m and σ p . In both plots most substituents fit well to a V-shaped Hammett plot (blue diamonds), suggesting that there are both meta and para effects. Interestingly, there are four clear outliers (red circles and green triangles). From the σ constants of the groups studied, it can be seen that those highlighted in blue have similar σ m and σ p values. In contrast, the groups in red and green have significantly different values for their σ m and σ p constants. For example, the OMe and OEt groups have negative σ p values (−0.27, −0.24) but positive σ m (0.12, 0.10). These two groups show higher reactivity than would be expected from Figure 3, where only their σ m or σ p are    3 base. Initial arylation rates in formation of 3cb were determined by GC-FID using hexadecane as internal standard.

Journal of the American Chemical Society
Article considered in isolation. This implies that opposite electronic effects are synergistically combining to lower the overall ΔG ⧧ , thus enhancing the arylation rate. These observations indicate that both σ m and σ p must be considered at the same time. This is reasonable in the system under study as both the kinetically relevant cyclometalation (III to IV) and the rate-limiting aryl bromide oxidative addition (IV to V) steps may be affected by electronic perturbation at the meta and para sites of the benzoate substrates ( ) at several points in the arylation process ( Figure 4). We return to deconvolute these meta and para effects in the computational section below. Importantly, considering the Hammett equation, eq 1, a Hammett plot should only result in a linear free energy relationship (LFER) if the electronic influence of the R group affects only one position of the aromatic (meta or para) of a kinetically relevant step (i.e., if ρ p σ p ≫ ρ m σ m or ρ m σ m ≫ ρ p σ p ).
Hammett equation: Although V-shaped Hammett plots are usually associated with a change in the mechanism of the process, 16 the lowering of the overall ΔG ⧧ due to a weighed variation of the electronic properties of the meta and para positions of the benzoates associated with the kinetically relevant cyclometalation provides a more logical explanation for our experimental data (see also the DFT studies below). To validate further this hypothesis, we applied Jaffe's analysis of the Hammett equation to our system. This modification allows the correlation of substituent perturbations that influence more than one reactive center at the same time to be plotted ( Figure  5). 17 In the Jafféequation, the Hammett equation is divided by one of the two σ values. Depending on which σ constant is in the denominator, the slope of the plot gives one ρ value, while the y-intercept provides the other ρ value (eqs 2 and 3). In order to verify the LFER, both plots should result in the same values of ρ m and ρ p . As shown in Figure 5, this treatment of the data led to two plots showing a LFER valid for all the substituents. Similar ρ values were obtained in both cases (ρ m ≅ 2.2; ρ p ≅ −1.2), thus validating our mechanistic framework. The magnitude of the ρ values indicates that the electronic perturbation on the C Ar −H/[Ru]−C Ar bonds (i.e., meta) has a greater effect on the overall rate. Furthermore, the signs of ρ m and ρ p indicate that the overall rate is enhanced by para-EDGs

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Article and by meta-EWGs, which is consistent with the observation that OMe and OEt substituents are visibly outliers in both Vshaped Hammett plots. Importantly, as the meta effect is more significant than the para one, it should also be noted that in the para V-shaped Hammett plot both OPh and F significantly deviate from linearity, as both rates are largely underestimated due to the greater contribution of the meta effect. Instead in the meta V-shaped Hammett plot OPh and F are marginally under-and overestimated, respectively. Although both substituents have positive σ m (F = 0.34, OPh = 0.25), OPh has a slightly negative σ p (−0.03), while F has a slightly positive one (0.06), which explains why OPh lies above and F below the linear fitting. (2) Jafféequation: 2.4. DFT Studies. We have also probed the mechanism of these benzoate-assisted arylation reactions with density functional theory (DFT) calculations. The reaction of a model system, [Ru(C 6 F 5 )(MeCN) 5 ] + (denoted II′), with PhBr in the presence of PhCO 2 − was considered, with all geometries optimized with the BP86 functional using a modest basis set (BS1, see Computational Details, SI, section 9). Energies were then recomputed using the ωB97X-D functional with a def2-TZVP basis set and incorporating MeCN solvation via a PCM correction. Test calculations indicated the use of MeCN in place of the t-BuCN ligands had little effect on the overall profile, with most stationary points being destabilized by 2−4 kcal/mol (see Figure S21). . This gives a cyclometalated species Int(III′−IV′)3 at +9.90 kcal/mol as a benzoic acid adduct. PhCO 2 H/MeCN substitution then forms fac-IV′ at +9.62 kcal/mol. 19 The overall barrier to C−H activation is 21.20 kcal/mol, and the formation of fac-IV′ is endergonic by 15.19 kcal/mol.
Alternative C−H bond activation mechanisms were also assessed and shown to be energetically less accessible (Figure 7 and Figure S8 and S9). Thus, transition states for external CMD at [Ru(C 6 F 5 )(MeCN) 3 (κ 1 -PhCO 2 )] by PhCO 2 − lie above 30 kcal/mol. A direct role for − OC(CF 3 ) 3 as a base in  Geometries of alternative C−H activation transition states with selected key distances in Å and relative free energies in kcal/mol (L = MeCN, Ar F = C 6 F 5 ). Geometric data for the external CMD transition state are for R = C(O)Ph; see SI for more details and alternative isomers (Figures S8 and S9).

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Article C−H activation was also ruled out, either as an external CMD process or as an intramolecular base (AMLA-4/CMD). We return to the role of − OC(CF 3 ) 3 in promoting the arylation reaction below.
Such processes, however, proved to have very large barriers. Instead a second MeCN ligand is lost to form squarepyramidal [Ru(C 6 F 5 )(MeCN)(κ-C,O-C 6 H 4 CO 2 )(κ-Br-PhBr)] − , Int(IV′−V′). This species has 12 possible geometric isomers of which 11 proved to be local minima (see Figure  S7); the lowest energy form is shown in Figure 6 and benefits from having the strong donor aryl ligand in the axial position as well as the weak PhBr ligand opposite the high trans influence C 6 F 5 . PhBr is computed to prefer binding through the Br substituent over alternative η 2 -C 6 H 5 Br forms, and IRC calculations subsequently confirmed that this Br-bound intermediate lies directly on the pathway for concerted oxidative addition. This proceeds via TS(IV′−V′) at 19.30 kcal/mol to give V′ at +11.27 kcal/mol. Ph−C 6 F 5 reductive coupling then readily occurs via TS(V′−VI′) at +14.38 kcal/ mol and gives Int(V′−VI′) (−19.44 kcal/mol) in which the biaryl product is bound in an η 2 -fashion to Ru. 20 The free energy profile for arylation in Figure 6 indicates that the overall rate-limiting process is associated with C−Br activation via TS(IV′−V′) at +19.30 kcal/mol and that this corresponds to an overall barrier of 24.87 kcal/mol. C−H activation is therefore a pre-equilibrium, the endergonic nature of which is consistent with reversible C−H activation leading to H/D exchange at the ortho position and a modest (equilibrium) kinetic isotope effect.
As discussed above and shown in Figure 7, the role of the − OC(CF 3 ) 3 additive in promoting arylation cannot be ascribed to any direct participation in the C−H activation event. Instead we postulate that − OC(CF 3 ) 3 affects the position of the C−H activation pre-equilibrium via deprotonation of the benzoic acid produced in this process. Based on the pK a values of PhCO 2 H and HOC(CF 3 ) 3 in water (4.2 and 5.2, respectively) this implies a free energy change of −1.4 kcal/ mol upon deprotonation. To quantify this effect, a kinetic model accommodating all the steps linking II′ to Int(V′−VI′) was constructed (see Figure 9a) where any ligand substitution processes were treated as dissociative in nature with the ligand addition steps assumed to occur at the diffusion-controlled limit (k = 10 10 M −1 s −1 , corresponding to a barrier of 4.78 kcal/mol at 363 K). This allows for the rate of the related ligand dissociation to be defined, based on the equilibrium constant computed for the overall ligand exchange. Within this model − OC(CF 3 ) 3 intervenes upon loss of PhCO 2 H from species I, and its effect is modeled by a 1.4 kcal/mol stabilization of all species from J onward (right-hand shaded area, Figure 9b). This leaves the rates of the onward reactions unchanged but reduces the rate of the backward reaction (i.e., J + PhCO 2 H → I). The effect is seen in Figure 9c, plot i, which shows that product formation (modeled by species N) is approximately doubled over a 1 h period in the presence of the − OC(CF 3 ) 3 additive (compare the dotted and solid red lines). This is in good agreement with experimental observations, which indicate a ca. 3-fold rate enhancement (Figure 1).
The profile in Figure 9b was recomputed with two substituted benzoates, 4-R-C 6 H 4 CO 2 − , with R = NMe 2 and CF 3 . These substituents have distinctly different σ p and σ m Hammett parameters, yet experimentally both provide significantly enhanced reactivity compared to the parent benzoate (Table 1). In each case, a similar overall profile was computed, with the transition state for C−Br activation lying above that for C−H activation (see Table 2 and Figures S12 and S13). The results again emphasize the sensitivity of the overall outcome to the inclusion of the − OC(CF 3 ) 3 additive in the model. This is more apparent for 4-CF 3 -C 6 H 4 CO 2 − for which a reduction of 2.16 kcal/mol in ΔG CHA leads to an order of magnitude reduction in the computed t 1/2 , the time required to reach 50% conversion. The higher pK a of 4-NMe 2 -C 6 H 4 CO 2 H means the effect here is less dramatic, but in this case, the computed barrier in the absence of − OC-(CF 3 ) 3 is already significantly lower than the PhCO 2 − / − OC-(CF 3 ) 3 system.
The data in Table 2 indicate that the overall barrier to arylation (ΔG span ⧧ ) depends more on the free energy change of the C−H activation (ΔG CHA ) rather than the subsequent barrier to PhBr activation (ΔG PhBr ⧧ ). The variation in ΔG CHA is mirrored in the trend in the 2-step C−H activation (G → I: R = NMe 2 (+12.23 kcal/mol) < R = CF 3 (+13.74 kcal/mol) < R = H (14.47 kcal/mol)). The fact that both an electrondonating and an electron-withdrawing substituent reduce the barrier to C−H activation over the unsubstituted parent has parallels in the trends computed by Gorelsky and Fagnou for C−H activation of (hetero)aromatics at Pd(Ph)(OAc)-(PMe 3 ), 4d,22 although the variations are much smaller here. The effect of the − OC(CF 3 ) 3 base is also a significant factor in accelerating the reaction, especially with the 4-CF 3 − C 6 H 4 CO 2 − additive. As highlighted in Figure 4, electronic perturbation arising from the benzoate substituent, R, could manifest itself at several points along the reaction pathway. The initial cyclometalation involves C Ar −H bond cleavage and formation of a C Ar −[Ru] bond, both of which should be sensitive to σ m ; similarly this process involves varying the C(O)O− [Ru] interaction and H + transfer to a second benzoate to form a C(O)O−H bond, which will be more dependent on σ p . As discussed above, the C−Br activation step shows little dependence on R, so we have focused on deconvoluting how σ m and σ p affect ΔG CHA . Figure 8. Geometries of alternative C−Br activation transition states with selected key distances in Å and relative free energies in kcal/mol (L = MeCN, Ar F = C 6 F 5 ). Examples shown are the lowest energy transition states located for each process; full details of isomers are in the SI (Figures S10 and S11). Data in parentheses are those where the PCM correction for acetonitrile solvent is included in the optimization procedure.

Article
To this end, we have computed the free energy changes for the model cyclometalation processes (eqs 4 and 5) for all the 4-R-C 6 H 4 CO 2 − substrates studied experimentally (see Figure  10 and Table S5). In eq 4 cyclometalation of the parent benzoate in E proceeds with different 4-R-C 6 H 4 CO 2 − acting as the base: ΔG(4) should therefore reflect how σ p promotes C− H activation. In eq 5, the cyclometalation of different 4-R-C 6 H 4 CO 2 − in E proceeds with the parent benzoate acting as the base. ΔG(5) should be dominated by the breaking of the C Ar −H bond and the formation of the new [Ru]−C Ar bond and, as such, should correlate with σ m . However, σ p may also play a role here by influencing how the C(O)O−[Ru] interaction varies due to the κ 2 −κ 1 change in substrate binding mode. This point was considered in process 6 and was found to be favored by electron-donating para-substituents. This effect is relatively weak, however, with a plot of ΔG(6) vs σ p giving a straight line of gradient 2.1 (R 2 = 0.92, see Graph S9).

Journal of the American Chemical Society
Article Plots of ΔG(4) versus σ p and ΔG(5) versus σ m are displayed in Figure 10. In both cases, a good correlation is found; moreover, the plots provide further evidence for the counterbalancing effects of the para-and meta-substituents. Thus, the cyclometalation is facilitated by electron-donating parasubstituents, which enhance substrate basicity (ΔG(4) versus σ p ), while for a given base substrate, cyclometalation is favored by electron-withdrawing meta-substituents (ΔG(5) versus σ m ). 23 Importantly, the gradients indicate the latter meta effect is approximately twice as large as the former para effect, in excellent agreement with the conclusions from the Jafféplots in Figure 5.
The trend in the meta effect as defined in eq 5 must relate to differences in the C Ar −H and [Ru]−C Ar bond energies. Direct computation of the C Ar −H homolytic bond dissociation energies shows little variation as a function of R, with most benzoates giving a value of 102 ± 0.5 kcal/mol (see SI, Table   S6). The [Ru]−C Ar bond strength must therefore dominate, with these being stronger with electron-withdrawing substituents. There is precedent for this in the selective C−H activation of fluoroarenes 24 and in M−C bond strengths being more sensitive to substituent effects than their equivalent C−H bonds. 25 2.5. The Role of Benzoate Cyclometalation in Promoting Arylation. Although the C−Br activation step proved insensitive to substituent effects on the benzoate, cyclometalation remains the key to making the overall arylation process accessible. To understand this more fully, C−Br activation was modeled at cationic, neutral, and noncyclometalated anionic analogues of L/Int(IV′−V′), and the most accessible processes for each case are shown in Figure 11. The data show two trends when moving from cationic through neutral and then to anionic systems: (i) the 5-coordinate precursor to C−Br activation becomes more accessible and (ii) the subsequent barrier to C−Br activation is reduced. Both factors make the overall barriers at [Ru(C 6 F 5 )-(MeCN) 3 (PhBr)] + and neutral [Ru(C 6 F 5 )(MeCN) 2 (κ 2 -PhCO 2 )(PhBr)] prohibitively high. This is still the case for [Ru(C 6 F 5 )(MeCN)(κ 1 -PhCO 2 ) 2 (PhBr)] − , 26 although interestingly for [Ru(C 6 F 5 )(κ 2 -PhCO 2 )(κ 1 -PhCO 2 ) 2 (PhBr)] − the barrier to C−Br activation falls to only 3.97 kcal/mol. This is in fact slightly lower than the barrier from cyclometalated L (4.08 kcal/mol), although in this case the low energy of L (+15.22 kcal/mol) allows C−Br activation to proceed via TS L−M /TS(IV′−V′) at only +19.30 kcal/mol. The role of the cyclometalated benzoate is therefore not just to enhance the electron-rich character of the Ru(II) center but also to facilitate ligand dissociation and thus render the 5-coordinate precursor to C−Br activation accessible. The high trans influence of the cyclometalated arm is therefore a key factor in promoting reactivity.
The cyclometalated benzoate ligand also plays an important role in dictating the selectivity of the C−C coupling process. The computed structures of the 6-coordinate Ru(IV) species such as intermediate M formed upon C−Br activation show a marked distortion away from an octahedral geometry, with a narrowing of the trans-C1−Ru−C2 bond that pushes one of the dπ orbitals up in energy (see Figure 12). 27 This distortion will tend to favor a low spin d 4 configuration, whereas geometries computed in the triplet state (which are often energetically competitive for these Ru(IV) species 28 ) exhibit more regular pseudo-octahedral structures.  Corrections for the effect of − OC(CF 3 ) 3 are based on the pK a values of HOC(CF 3 ) 3 (5.2) and PhCO 2 H (4.2) in water; pK a values for the 4-R-C 6 H 4 CO 2 H acids (R = NMe 2 , 5.03; R = CF 3 , 3.66) are based on the difference in the σ p Hammett parameters and the relationship σ = −(pK a (4-R-C 6 H 4 CO 2 H) − pK a (PhCO 2 H)).

Journal of the American Chemical Society
Article Distortion of the singlet is most favorable when strong σdonors adopt a mutually trans arrangement, so the most stable isomers of Ru(IV) species M feature the three strongly donating aryl ligands in a mer configuration. One of these, M(ii), has Ph trans to C 6 F 5 and is actually more stable than M itself (see Figure 13); moreover C−C coupling with the benzoate ligand in M(ii) proceeds through a lower transition state, TS M(ii)−N(ii) (+11.76 kcal/mol), than that for Ph−C 6 F 5 coupling via TS M−N (+14.38 kcal/mol). The fact that benzoate−Ph coupling is not observed is due to M(ii) being kinetically inaccessible, either through C−Br activation at L(ii) (via TS L(ii)−M(ii) , +27.63 kcal/mol) or through isomerization of M. The lowest energy isomerization pathway involves Br − loss to form the neutral trigonal bipyramidal intermediate I M−M(ii) followed by Br − reassociation to give M(ii); this second step involves transition state TS M−M(ii)2 , which at 17.63 kcal/mol is >3 kcal/mol higher than TS M−N at 14.38 kcal/mol. Benzoate− C 6 F 5 coupling from either M or M(ii) is also significantly less accessible (see Figure S20). More generally, for the systems in Figure 11 that lack a cyclometalated ligand, C−Br activation is computed to be more accessible when the Ph ligand moves trans to C 6 F 5 . The presence of the cyclometalated benzoate therefore promotes the formation of a Ru(IV) intermediate where the Ph and C 6 F 5 can be mutually cis, thus facilitating the observed selectivity of the subsequent C−C coupling.
The computed data highlight how a C−H functionalization process can be promoted through use of a base additive such as (NMe 4 )OC(CF 3 ) 3 and how a subtle perturbation of a C−H activation pre-equilibrium step can have a significant effect on the overall reaction efficiency. Group 1 carbonate salts, M 2 CO 3 , have often been proposed as proton sinks in direct arylation reactions, 29 and the choice of the Group 1 M + cation can significantly impact the end result when expressed as a reaction yield. The results here highlight how such variations can result from small changes in the efficiency of these processes that could reflect, for example, changes in additive concentration due to varying solubilities in organic reaction media.

CONCLUSIONS
A detailed experimental and in silico mechanistic investigation allowed the elucidation of the role of the benzoate salt in promoting aryl halide oxidative addition in the Ru(II)catalyzed C−H arylation of fluoroarenes. The inability of 2,6-disubstituted benzoate sources to trigger the desired arylation event, along with D/H scrambling and kinetic isotope effect experiments, supported the hypothesis for the requirement of a cyclometalation step of the benzoate salt. Thus, the resulting highly electron-rich anionic Ru(II) intermediate rapidly undergoes oxidative addition with the Figure 11. Lowest energy pathways (kcal/mol, L = MeCN, Ar F = C 6 F 5 ) computed for C−Br activation at 5-coordinate cationic, neutral, and anionic precursors, placing the Ph group cis to C 6 F 5 . a Proceeds via nucleophilic displacement of Br − ; all other pathways involve a concerted oxidative addition. See Figures S15−S19 for details and alternative pathways.

Journal of the American Chemical Society
Article aryl halide to furnish the biaryl product via a selective reductive elimination step. The pre-equilibrium associated with the kinetically relevant benzoate cyclometalation leads to a Jaffeŕ elationship reflecting the influence of the benzoate substituents at multiple distinctive sites in this process. Indeed, simple Hammett plots correlating the electronic perturbation at only one reactive site at the time could not provide a linear free energy relationship that accommodated all the substituents studied.
DFT calculations provide support for a mechanism involving reversible C−H activation and formation of an anionic cyclometalated intermediate. The enhanced lability of this species allows access to a reactive 5-coordinate intermediate capable of C−Br bond cleavage. A kinetic model based on the computed mechanism captures the rate enhancement observed with p-substituted benzoates bearing both electron withdrawing and electron donating substituents. The role of a (NMe 4 )OC(CF 3 ) 3 additive in promoting reactivity is pinpointed to the deprotonation of the carboxylic acid formed upon cyclometalation that shifts the pre-equilibrium associated with benzoate cyclometalation. This effect is particularly marked for less basic benzoates such as (NMe 4 )(4-CF 3 -C 6 H 4 CO 2 ), the conjugate acids of which will be more readily deprotonated by the (NMe 4 )OC(CF 3 ) 3 additive. Both the experimental and computational results highlight the counterbalancing effects of electron-withdrawing groups meta to the site of benzoate cyclometalation and electron-donating groups para to the proton-accepting carboxylate group in promoting reactivity, with the former having the larger influence by a factor of approximately 2.
Finally, this mechanistic breakthrough has important implications on the design of new catalytic systems involving an oxidative addition at Ru(II) centers, which have been significantly underdeveloped due to the lack of knowledge surrounding this fundamental step.