Mechanistic Duality in Palladium-Catalyzed, Cross-Coupling Reactions of Aryldimethylsilanolates. The Intermediacy of an 8-Si-4 Arylpalladium(II) Silanolate

Abstract

The mechanism of palladium-catalyzed cross-coupling reactions of potassium aryl(dimethyl)silanolate K⁺1⁻ has been investigated. Under catalysis by (t-Bu₃P)₂Pd the coupling with 2-bromofluorobenzene (2) displays the following rate equation: rate = k_obs[R₃SiOK]⁰[ArylBr]⁰ with k_obs = k[(t-Bu₃P)₂Pd]^0.98. An independent study of the individual steps of the catalytic cycle has revealed a dual mechanistic pathway. The transmetalation can occur by a thermal process via an 8-Si-4 intermediate without the need for anionic activation. Additionally, arylsilanolates can serve as activators for transmetalation via a hypervalent 10-Si-5 siliconate intermediate.

Palladium-(and nickel-)catalyzed cross-coupling reactions have emerged as the premier methods for construction of carbon-carbon (and carbon-heteroatom) bonds between unsaturated organic moieties. The historical development, diversification and applications of the myriad variants of this process are amply chronicled in recent monographs and authoritative volumes.¹ The generally accepted mechanism for these transition-metal-catalyzed, cross-coupling reactions involve: (1) oxidative addition to an electrophilic halide or pseudo halide (2) transmetalation from an organometallic donor and (3) reductive elimination to generate a new C-X bond. Although the oxidative addition of an organic halide to a Pd(0) complex is common among most coupling reactions, the transmetalation step is distinctive to the organometallic donor employed. The transmetalation of organostannanes has been extensively studied but is still a matter of some debate.² These transfers have been suggested to follow an inter-molecular S_E2 mechanism by means of stereochemical models. Similarly, organosilane transmetalations can proceed via either a four-centered, closed transition structure (retentive) or an acyclic, open process (invertive).³ Cross-coupling reactions of organoboranes are highly base dependent and a pre-coordination of the transferring agent with the transition metal followed by delivery has been proposed for the transmetalation step.⁴, Although kinetic studies have provided independent evidence for these pathways, the ability to isolate and characterize pre-transmetalation precursors is needed to unambiguously establish the course of palladium-catalyzed, cross-coupling reactions.^5,6

Recent kinetic investigations from these laboratories on the mechanism of palladium-catalyzed cross-coupling with alkenyl(dimethyl)silanols⁷ revealed that the transmetalation step is dependent on the reaction conditions. Cross-coupling of (E)-dimethyl(1-heptenyl)silanol under “classical activation”⁸ by TBAF proceeds via a pentacoordinate siliconate complex that engages in a bimolecular transmetalation with the organoPd(II)-X acceptor.^9a However, in a second mechanistic study, the observation of saturation kinetics suggested that upon silanol deprotonation, the resulting silanolate (iia) forms an adduct (iiia) with the organoPd(II)-X intermediate (i) from which (turnover limiting) transmetalation occurs spontaneously (Figure 1).^9b Because, this latter conclusion violated the reigning dogma that transmetalation from silicon to palladium required an anionic siliconate species,⁸ we sought to independently document this new pathway through the isolation and characterization of the palladium silanolate complex and establish the mechanistic relevance of this intermediate.

Figure 1.

Mechanistic proposal for the coupling of alkenyl- and aryldimethylsilanolates.

The unexpectedly facile transmetalation from the putative alkenyl(dimethyl)Si–O–Pd(aryl) species iiia precluded its isolation and demonstration of its kinetic behavior. However, we hypothesized that such an intermediate might be isolable by employing an arylsilanolate as the nucleophilic partner because cross-coupling reactions of these species require elevated temperatures and proceed via a slower transmetalation step.¹⁰ Moreover, the use of strongly coordinating phosphine ligands might also stabilize the intermediate iiib and allow for its isolation. Fortunately, both of these requirements are met in a recent disclosure from these laboratories which reported the cross-coupling of arylsilanolates with aryl halides using bis(tri-tert-butyl)phosphine palladium(0).¹¹ The isolation of stable, T-shaped complexes of arylpalladium halides and alkoxides ligated with (t-Bu)₃P¹² suggested that the arylsilanolate complexes could also be sufficiently stable for isolation. We report herein the isolation and characterization of a stable (8-Si-4) complex containing a Pd-O-Si linkage that has allowed the identification of two, distinct mechanistic pathways for the cross-coupling of arylsilanolates.

First, to vouchsafe that the arylsilanolate cross-coupling was proceeding in a transmetalation-limiting regime, we determined the rate equation for the cross-coupling of potassium (4-methoxyphenyl)dimethyl silanolate (K⁺1⁻) with 4-fluorobromobenzene (2) catalyzed by (t-Bu₃P)₂Pd. The partial order in each component in the reaction was determined individually at 95 °C in toluene (Scheme 1) using ¹⁹F NMR analysis. Kinetic rates were determined from the slope of the plot of the loss of aryl bromide over time as determined through > 3 half lives.¹³

Scheme 1.

The partial order in silanolate was obtained by comparison of the initial rates of consumption of aryl bromide versus 75, 150 and 300 mM concentrations of K⁺1⁻. An overlay of the linear plots of the kinetic data clearly shows no effect on the concentration of K⁺1⁻ and establishes zeroth-order behavior for this component. Next, the rate dependence on [2] was similarly established to be zeroth order using concentrations of 100, 200 and 400 mM for this component. Finally, the rate dependence on the amount of the palladium catalyst was determined by comparison of the rate constant (k_obs) versus 0.05, 0.10, 0.15 and 0.20 equiv of (t-Bu₃P)₂Pd at 100 mM in 2. A positive slope of 0.979 obtained from a log plot of k_obs versus [Pd] is consistent with a first order dependence of the observed rate constant on the concentration of palladium. Thus, the overall rate equation for the reaction of K⁺1⁻ with 2 catalyzed by (t-Bu₃P)₂Pd is shown in equation 1 (with a rate of 1.06 × 10^-2 mMs^-1). This rate equation matches that of the alkenylsilanolates reported previously^9b and we thus conclude that here as well, a turnover-limiting, transmetalation from an arylpalladium(II) intermediate is taking place. However, this rate equation cannot differentiate between direct transmetalation via iiib or activated transmetalation via ivb.¹⁴ Accordingly, if transmetalation is indeed the turnover-limiting step, then either arylpalladium(II)silanolate complex iiib or ivb should be detectable. However, ³¹P NMR analysis of the reaction mixtures showed that the predominant phosphine-containing species was the PdL₂ catalyst (δ ³¹P, 85.4 ppm).¹⁵ A plausible explanation for this behavior is that the signal for the palladium silanolate complex is broadened at elevated temperatures and is not visible. Thus, to gain insight into the individual steps in the catalytic cycle, our attention shifted to investigating these events stoichiometrically.

$$-\text{d}\left[\mathbf{2}\right]/\text{dt}={\text{k}}_{\text{obs}}{\left[{\text{K}}^{+}{\mathbf{1}}^{-}\right]}^0{\left[\mathbf{2}\right]}^0\text{with}{\text{k}}_{\text{obs}}=\text{k}{\left[\text{Pd}\right]}^{0.98}$$ (1)

The independent synthesis of the proposed intermediate iiib began with the preparation of the oxidative addition complex.^12a Treating (t-Bu₃P)₂Pd with an excess of 2 resulted in the formation of the T-shaped, monomeric complex (t-Bu₃P)(4-FC₆H₄)PdBr (4) which could be isolated and spectroscopically characterized. Next, the displacement step was simulated by adding an equimolar quantity of K⁺1⁻ to a solution of 4 in toluene. Inspection of both the ³¹P and ¹⁹F NMR spectra of the mixture revealed no observable changes of the diagnostic resonances. Even after 30 min, only a single species was present that appeared to be the starting complex 4.¹⁶ However, inspection of the ¹H NMR spectrum of this solution revealed that chemical shift of the methyl groups on silicon had changed and that two new aryl proton signals appeared. This new species was spectroscopically identified as the proposed aryl palladium(II)silanolate complex 5.

Ultimately, the structure of adduct 5 was confirmed by isolation and single crystal X-ray analysis (Figure 2).^{12c, 17a} The Pd(1)-O(1) bond length (2.02 Å) is similar to those previously observed for palladium(II) silanolates.¹⁸ Furthermore, the Si(1)-O(1) bond length is typical for silanolates which suggests that the ligand effect at the palladium center is not as substantial compared to other bisphosphine palladium(II)silanolate complexes.^17b A weak agostic interaction between one of the H atoms of a t-Bu methyl group and the palladium is noted. In addition, the Pd(1)-O(1)-Si(1) angle of 128.5° is considerably more acute compared to other known palladium(II)¹⁸ and platinum(II)⁶ silanolates and the nonbonded distance between the silicon-bearing ipso carbon and the palladium atom (3.70 Å) hints to a weak interaction that anticipates the transmetalation event.

Figure 2.

X-ray crystal structure of complex 5. Hydrogens removed for clarity.

With the desired palladium(II)silanolate complex in hand, we were poised to study the transmetalation process. Simply heating complex 5 (formed in situ) in toluene at 50 °C resulted in the formation of the biaryl product in 80-90% yields with concomitant formation of PdL₂ (Scheme 2).^19,20 The thermal transmetalation process followed a first order decay with a k_obs of 5.0 × 10^-4 s^-1. Because the starting palladium catalyst has a 2:1 ligand/palladium ratio, the stoichiometric transmetalation was performed in the presence of t-Bu₃P to establish if a partial order in ligand could be detected as well. Heating a solution of complex 5 in the presence of 1.0 and 5.0 equiv of t-Bu₃P led to a clean reaction with rate constants of 4.7 × 10^-4 s^-1 and 4.9 × 10^-4 s^-1, respectively. Thus, the similar rate constants for the thermal reaction at varying concentrations of free phosphine clearly indicate a zeroth order concentration dependence for the ligand. These data suggest that phosphine dissociation is not required for transmetalation and that the arene simply transfers to the open coordination site on palladium directly. These experiments provide further evidence of an unactivated, thermal transmetalation pathway for silicon-based, cross-coupling reactions.

Scheme 2.

For these kinetic studies described above, the palladium(II)silanolate complex was generated in situ for ease of manipulation. However, in a few instances the rapid formation of biaryl products was observed at room temperature. To elucidate the origin of these anomalously fast reactions, complex 5 was treated with K⁺1⁻ (1.0 equiv) and 3 was formed in excellent yield (>90%) at room temperature! Because the catalytic reaction is necessarily performed with a large excess of silanolate with respect to palladium, a kinetic study was undertaken to compare the rates of transmetalation of these different processes. Therefore, treating 5 with 1.0 equiv of K⁺1⁻ at 50 °C afforded the biaryl product with a k_obs of 5.0 × 10^-3 s^-1. This observed rate constant corresponds to a 10-fold increase compared to the thermal process established above. These data suggest that an activation-type pathway via a 10-Si-5 complex may also be operative.

If, in fact, the silanolate is opening a pathway for activated transmetalation, then modulating the nucleophilicity of the arylsilanolate should manifest in an observable change in rate. Thus, when the cesium salt of 1 was employed in combination with 5 at 50 °C, product formation was so fast that the rate could not be measured. To compare the rates of transmetalation using different silanolates, the reaction was instead performed at room temperature (21 °C). Scheme 3 clearly shows that Cs⁺1⁻ leads to a more rapid consumption of 5 to afford the unsymmetrical biaryl product. In fact, the rate constant for the Cs⁺1⁻ induced reaction was 4.5 times larger than that for K⁺1⁻. These data suggest that the increased nucleophilicity of the arylsilanolate plays a role in the formation of the 10-Si-5 siliconate intermediate. Furthermore, the kinetic dependence on [Cs⁺1^-] was determined by comparing the rate constants for the reaction in Scheme 3 at 6.6, 12.5 and 25 mM. A log plot of the k_obs versus concentration clearly shows a first order dependence and provides additional support for the activated pathway.²¹ Once the palladium(II)silanolate is formed from a fast displacement step, a second molecule of Cs⁺1^- is required to activate the silicon atom toward transmetalation.

Scheme 3.

By combining the results from both the kinetic studies and the stoichiometric experiments, a detailed mechanism for the cross-coupling of arylsilanolates can be formulated that illustrates how both thermal and anionic pathways can operate simultaneously (Figure 3). To initiate the cycle (green), oxidative addition occurs directly from (t-Bu₃P)₂Pd to generate the monomeric T-shaped complex, ib.²² Rapid displacement of the halide occurs in which the key Pd-O-Si moiety is forged with loss of the M⁺X⁻ salt. Now poised for transmetalation, iiib can proceed down two independent pathways that involve either (1) a thermal intramolecular transmetalation (8-Si-4, depicted in blue) or (2) an anionically activated pathway involving the formation of a hypervalent siliconate (ivb, 10-Si-5, depicted in red). Because under catalytic conditions, an excess of silanolate is employed, we conclude that the cross-coupling likely proceeds via the activation pathway.

Figure 3.

Mechanism for the Cross-Coupling of Arylsilanolates

In conclusion, the mechanistic landscape of the cross-coupling of arylsilanolates with aryl halides has been refined. The isolation and characterization of a palladium silanolate complex allowed for the discovery of both thermal and anionic mechanistic pathways for transmetalation from silicon to palladium. The ability to isolate palladium silanolate intermediates will enable further studies on molecular details of the transmetalation event.