The Potassium Trimethylsilanolate-Promoted, Anhydrous Suzuki-Miyaura Cross-Coupling Reaction Proceeds via the “Boronate Mechanism”: Evidence for the Alternative Fork in the Trail

Abstract

Previous studies have shown that the critical transmetalation step in the Suzuki-Miyaura cross-coupling proceeds through a mechanism wherein an arylpalladium hydroxide complex reacts with an aryl boronic acid, termed the oxo-palladium pathway. Moreover, these same studies have established that the reaction between an aryl boronate and an arylpalladium halide complex (the boronate pathway) is prohibitively slow. Herein, studies on isolated intermediates, along with kinetic analysis have demonstrated that the Suzuki-Miyaura reaction promoted by potassium trimethylsilanolate (TMSOK) proceeds through the boronate pathway, in contrast with other, established systems. Furthermore, an unprecedented, binuclear palladium(I) complex containing a μ-phenyl bridging ligand was characterized through NMR spectroscopy, mass spectrometry and computational methods. DFT calculations suggest the binuclear complex exhibits an open-shell ground electronic state, and reaction kinetics implicate the complex in the catalytic cycle. These results expand the breadth of potential mechanisms by which the Suzuki-Miyaura reaction can occur, and the novel binuclear palladium complex discovered has broad implications for palladium-mediated cross-coupling reactions of aryl halides.

Graphical Abstract

1. INTRODUCTION

The development of transition-metal catalyzed, cross-coupling reactions has fundamentally changed the way chemists construct C–C bonds.¹ Because the formation of C–C bonds is central to synthetic organic chemistry, cross-coupling reactions are routinely applied in nearly every field in which organic chemistry is relevant, including polymer and materials chemistry,² medicinal chemistry,³ small-molecule synthesis performed on small scale⁴ and large,⁵ and natural products synthesis.⁶ The widespread impact of this technology was recognized by the 2010 Nobel Prize in Chemistry, awarded to Richard Heck, Ei-ichi Negishi, and Akira Suzuki for their pioneering studies on cross-coupling reactions.^1,7 Among cross-coupling reactions that form C–C bonds, the Suzuki-Miyaura cross-coupling⁸ has emerged as the most powerful method – this fact is reflected in its status as the most commonly used C–C bond forming reaction in the pharmaceutical industry.^1,3a

Given the importance of the Suzuki-Miyaura reaction, the mechanism by which it proceeds is of considerable interest, as mechanistic understanding allows chemists to better optimize the process. At the most basic level, the Suzuki-Miyaura reaction involves three steps – oxidative addition, transmetalation, and reductive elimination.⁹ Following advances in ligand design, transmetalation is frequently implicated as the turnover-limiting step in the Suzuki-Miyaura reaction, and therefore the mechanism of transmetalation is particularly important.^8f,10 It has long been hypothesized that transmetalation in the Suzuki-Miyaura reaction proceeds through the intermediacy of a Pd-O-B linked intermediate, with an oxyanionic base acting as a bridge between palladium and boron.¹¹ However, the mechanism by which such a Pd-O-B linked species is formed has been the subject of much debate.¹⁰ The two common hypotheses for the mechanism of Pd-O-B formation are termed the boronate pathway (path A) and the oxo-palladium pathway (path B) (Scheme 1).¹² In the boronate pathway, a 4-coordinate, 8-electron boronate species (8-B-4)¹³ reacts with an arylpalladium halide complex, displacing the halogen and forming the pre-transmetalation intermediate. In the oxo-palladium pathway, the arylpalladium halide complex first undergoes exchange with a base in solution to form an arylpalladium hydroxide complex that often spontaneously dimerizes. The resulting arylpalladium hydroxide dimer then reacts with a 6-electron, 3-coordinate boron compound (6-B-3), forming the same pre-transmetalation intermediate (Scheme 1).

Scheme 1.

Pre-transmetalation Pathways in the Suzuki-Miyaura Reaction.

Studies that seek to differentiate between the boronate and oxo-palladium pathways are often hampered by heterogeneous reaction conditions originating from either: (1) the biphasic aqueous/organic mixture typically employed in Suzuki-Miyaura reactions, or (2) the insolubility of boronate salts in commonly used organic solvents. Despite these challenges, several experimental studies have demonstrated that the oxo-palladium pathway is operative in most Suzuki-Miyaura reactions. In one such study conducted by Amatore, Jutand, and Le Duc, the dependence of reaction rate on the concentration of boronic acid and tetrabutylammonium hydroxide was cited as evidence for an oxo-palladium mechanism (Scheme 2).¹⁴ At low base concentration, a positive rate dependence on the mole fraction of boronate was observed. However, as the mole fraction of boronate approaches unity, the rate of reaction slows. Amatore, Jutand, and Le Duc hypothesize that the rate initially increases with the concentration of boronate because the base is needed to promote the formation of arylpalladium hydroxide complex 2. However, as more base is added, increased conversion of competent, 6-B-3 boronic acid 3 into incompetent 8-B-4 boronate species 4 causes the rate of reaction to decrease.

Scheme 2.

Mechanistic Experiments by Amatore, Jutand, and Le Duc that Support Transmetalation Through the Oxo-Palladium Pathway.¹⁴

In another definitive study, Hartwig and Carrow directly compared the reactivities of catalytic intermediates implicated in the oxo-palladium and boronate pathways (Scheme 3).¹² The rate of transmetalation through the boronate pathway was determined by combining bis(triphenylphosphine)arylpalladium halide complex 6 with potassium boronate 7 in the presence of 18-crown-6, and the rate of reaction to form biaryl 8 was measured. To explore the oxo-palladium pathway, triphenylphosphine-ligated arylpalladium hydroxide dimer 9 was mixed with arylboronic acid 10. Hartwig and Carrow found that the oxo-palladium pathway kinetically outpaced the boronate pathway by several orders of magnitude.

Scheme 3.

Mechanistic Experiments from Hartwig and Carrow that Support Transmetalation Through the Oxo-Palladium Pathway.¹²

In contrast, examples of transmetalation through the boronate pathway are rare. Matos and Soderquist found that alkylboranes transmetalate through the boronate pathway.¹¹ Computational studies by Ortuño, Lledós, Maseras and Ujaque further suggest that the boronate pathway may be viable in some Suzuki-Miyaura reactions that cross-couple boronic acids.¹⁵ Finally, Lima, Rodrigues, Silva, Silva, and Santos use competition experiments to support a boronate mechanism for the Suzuki-Miyaura reaction.¹⁶

2. BACKGROUND

2.1. Influence of Boronic Ester Structure on Boron-to-Palladium Transmetalation Rate.

Although the intermediacy of Pd-O-B linked pre-transmetalation intermediates in the Suzuki-Miyaura reaction has long been hypothesized, no such complex had been identified or characterized until 2016, when Denmark and Thomas used their Rapid-Injection NMR (RI-NMR) apparatus¹⁷ to generate and spectroscopically characterize the pre-transmetalation intermediates in the Suzuki-Miyaura reaction.¹⁸ During the course of that investigation, a Pd-O-B linked complex incorporating a dimethyl boronic ester (13) was serendipitously discovered, characterized, and found to undergo transmetalation without prior hydrolysis to the boronic acid (Scheme 4).

Scheme 4.

Serendipitous Discovery of Dimethyl Boronic Ester-Containing preTransmetalation Intermediate 12.

Following the successful formation of pre-transmetalation intermediates that incorporate methyl boronic esters, it was logical to determine whether pre-transmetalation intermediates could be formed that incorporate other boronic esters (Figure 1).¹⁹ The combination of catechol boronic ester 15 with palladium hydroxide dimer 11 results in the formation of a new Pd-O-B intermediate incorporating the catechol ester. Likewise, a new Pd-O-B intermediate is formed when glycol boronic ester 16 is combined with 11. Each complex was freshly formed and warmed to −30 °C, at which temperature transmetalation takes place. Interestingly, the catechol ester 15 transmetalates 4x faster than the boronic acid 12, and both the glycol ester 16 and dimethyl ester 17 react more than 20x faster than 12. The observation that boronic ester structure influences the rate of transmetalation suggests that boronic ester structure can be used as a point of optimization alongside ligand and precatalyst selection, which elevates boronic esters beyond their traditional use as protecting groups. For this insight to be of use, it is imperative to demonstrate that the rate increase can be harnessed in a preparative reaction. Thus, a method was developed to cross-couple boronic esters with the express intent of leveraging boronic ester identity to increase reaction rate.

Figure 1.

Enhanced rate of transmetalation in complexes incorporating boronic esters.

2.2. Development of an Anhydrous, Homogeneous, Suzuki-Miyaura Cross-Coupling of Boronic Esters.

To develop the aforementioned method, it was decided that anhydrous reaction conditions would be optimal to prevent undesired ester hydrolysis. However, initial investigations using inorganic bases commonly employed in Suzuki-Miyaura reactions were hampered by the insolubility of these bases in aprotic solvents. Inspired by prior work in the Denmark laboratory on cross-coupling reactions of organosilicon reagents,²⁰ potassium trimethylsilanolate (TMSOK) was identified as a base to promote the homogeneous, anhydrous Suzuki-Miyaura cross-coupling of boronic esters (Scheme 5). It was demonstrated that the reaction time for several example reactions could be shortened from days to hours, without changing the ligand or precatalyst, simply by employing an appropriate boronic ester as the nucleophile, TMSOK as the base, and anhydrous, ethereal solvent.²¹ The homogeneous, anhydrous reaction conditions have also been adapted to the cross-coupling of heteroaryl nucleophiles with heteroaryl electrophiles, wherein the use of aqueous conditions can facilitate protodeboronation.^22,23

Scheme 5.

Homogeneous, Anhydrous Suzuki-Miyaura Reaction Promoted by TMSOK.²¹

As mentioned previously, the Suzuki-Miyaura reaction is frequently carried out using boronate complexes that are poorly soluble in organic media. In contrast, TMSOK-ligated boronates are highly soluble in THF. It was of interest to uncover what effect a soluble boronate has on the reaction mechanism, particularly with regard to the formation of a Pd-O-B intermediate. Furthermore, an explanation was sought for an anomaly uncovered during reaction optimization, namely, a stark dependence of product yield on base stoichiometry was observed. As the concentration of base exceeds the concentration of boronic ester, the reaction rate drops precipitously, with <30% yield observed when using 2.0 equiv or more base.²¹ Finally, the structure of the Pd-O-B linked intermediate was of interest, given that TMSOK is a much poorer bridging ligand than hydroxide. With that in mind, the following goals were identified for this study:

1. determine what mechanistic features lead to the observed dependence of reaction rate on base stoichiometry,

2. identify pre-transmetalation intermediates incorporating TMSOK and neopentyl boronic esters, and

3. determine if transmetalation proceeds through a boronate or oxo-palladium mechanism.

3. RESULTS

3.1. Stoichiometric Experiments Probing the Mechanism of Transmetalation.

3.1.1. Experimental Design.

Three potential transmetalation mechanisms were explored by studying reactions of isolated catalytic intermediates (Scheme 6) – the boronate pathway (path A), the oxo-palladium pathway (path B), and a third scenario termed path C, wherein a molecule of boronate reacts with an arylpalladium silanolate complex. First, reactivity through the boronate pathway (path A) was explored by combining a TMSOK-ligated, 8-B-4 boron reagent with an arylpalladium halide complex and observing the resulting reactivity. Second, the oxo-palladium pathway (path B) was explored by attempting to generate an arylpalladium silanolate complex and then combine it with a 6-B-3 boronic ester. Finally, path C was investigated by combining an arylpalladium silanolate complex with 8-B-4 boronate. In each case, the reaction was monitored using ¹⁹F NMR spectroscopy, allowing for the detection of any new species formed while simultaneously monitoring the concentration of the various species in solution.

Scheme 6.

Three Proposed Reaction Pathways That Were Investigated.

3.1.2. Investigation of Transmetalation Through the Boronate Pathway.

To test the boronate pathway (path A), 4-F-C₆H₄Pd[P(t-Bu)₃]Br (18) was combined with 1.0 equiv of TMSOK-ligated boronate complex of neopentyl 3,5-bistrifluoromethylphenylboronic ester (19) at −40 °C in THF. The combined reagents readily reacted at −40 °C to ultimately generate biaryl 20 following transmetalation and reductive elimination (Figure 2). No pre-transmetalation complex was observed, implying that the reaction is either intermolecular, that binding of boronate to the palladium complex is rate determining, or that the reaction follows Michaelis-Menten kinetics with a large value of K_M.

Figure 2.

Plot of concentration of reaction components vs time during transmetalation through the boronate pathway.

The concentration of various species in the reaction mixture was monitored over the course of 23 minutes at −40 °C using ¹⁹F NMR spectroscopy. After 23 minutes, all of palladium complex 18 had been consumed, but the concentration of biaryl product 20 was lower than expected and boronate 19 was only partially consumed. Furthermore, a new, unidentified species (23) characterized by a ¹⁹F NMR signal at −127.5 ppm was formed alongside the biaryl product 20.

The observation that boronate complex 19 reacts with Pd complex 18 to form biaryl 20 at −40 °C demonstrates that transmetalation through the boronate pathway is kinetically accessible in this system. This observation stands in contrast to prior results obtained using boronic acids under Hartwig and Carrow’s reaction conditions, in which the boronate pathway was prohibitively slow.¹² The high rate of transmetalation at −40 °C is also noteworthy. However, these findings were complicated by the appearance of species 23. Examining the reaction stoichiometry revealed that for each equiv of boronate 19 consumed, two equiv of Pd complex 18 were consumed. Correspondingly, one equiv of biaryl product 20 and one equiv of unknown 23 were formed.

In view of the observed stoichiometry and the consistently equimolar concentration of 20 and 23 over time (Figure 2), it was hypothesized that unknown complex 23 could be formed through a reaction between a post-reductive elimination reaction byproduct and the arylpalladium halide complex 18. With biaryl 20 accounted for in the ¹⁹F NMR spectrum, possible candidates for this reaction byproduct are P(t-Bu)₃Pd(0) (24) and boron byproduct 25 (Figure 3). To further elucidate the structure of the unidentified complex, it was characterized using a variety of 1-D and 2-D NMR spectroscopy techniques.

Figure 3.

¹H NMR spectrum of unknown species 23, biaryl 14 and boron byproduct 25.

3.1.3. Characterization of Unknown 23 Through NMR Spectroscopy.

Attempts to isolate complex 23 were unsuccessful, as it was observed to decompose at temperatures above −10 °C. Instead, a fresh sample was generated in situ, and spectroscopic characterization of the new complex 23 as a component of the product mixture was performed by means of ¹H, ¹⁹F, ³¹P, and ¹³C NMR spectroscopy alongside 2-D experiments including COSY, ROESY, HSQC, and HMBC. The boronate reagent used to synthesize 23 does not appear to influence the structure or yield of the product complex. Spectra of 23 generated by combination of arylpalladium bromide 18 with boronate 26 were identical to spectra of 23 generated from 18 and boronate 19, excepting the resonances associated with the biaryl product 14 or 20. The ¹H spectrum shown below (Figure 3) is of a reaction mixture wherein 26 was used as the boronate reagent.

In the aryl region of the ¹H NMR spectrum, resonances associated with biaryl 14 are observed at 7.65 and 7.18 ppm, integrating to four protons each. Two additional resonances at 6.85 and 6.58 ppm are assigned to the unknown complex. In the alkyl region, peaks consistent with boron byproduct 25 are observed at 3.61, 0.92, and 0.14 ppm. Finally, the singlet at 1.29 ppm integrating to 54 protons was assigned to two chemically equivalent P(t-Bu)₃ ligands. The chemical equivalence of the phosphine ligands is corroborated by the observation of one major peak at 77.3 ppm by ³¹P NMR analysis. The remaining signals are assigned as a small quantity of residual 26.

COSY, HSQC, and HMBC spectra were obtained for the mixture in THF-d₈ but were not structurally informative. However, the ROESY spectrum contained a cross-peak demonstrating polarization transfer between the P(t-Bu)₃ protons and both ortho and meta 4-F-C₆H₄ protons, suggesting the ligand and arene are both part of one molecule, and not two components of a mixture. Full characterization data is provided in the Supporting Information.

Taken together, these data suggest that the unknown complex contains a 4-fluorophenyl group, and two symmetrically related tri-tert-butylphosphine groups. We hypothesize such a complex could be produced if the highly reactive complex P(t-Bu)₃Pd(0) generated following reductive elimination combined with arylpalladium bromide complex 18 to form a new, binuclear palladium complex (Scheme 7). To further test this hypothesis, mass spectrometry was used to establish composition of matter and gain further structural information.

Scheme 7.

Proposed Structure of Unknown 23 Characterized by ¹⁹F Peak at −127.5 ppm.

3.1.4. Mass Spectrometric Characterization of 23.

The temperature sensitivity of complex 23 and the low dielectric constant of THF created several challenges in the characterization by mass spectrometry. We employed a modified pressurized sample infusion (PSI) air-free sampling technique developed by McIndoe²⁴ by modeling a cold electrospray ionization (CSI) apparatus developed by Yamaguchi et al.²⁵ to ensure that the reaction mixture could be maintained under inert atmosphere below −20 °C until ions reached the gas phase. The sampling apparatus and conditions for all MS experiments are detailed in the supporting information. As 23 had been previously generated and characterized in THF, a sub-optimal solvent for electrospray ionization, we utilized ¹⁹F NMR spectroscopy to confirm that complex 23, once generated as a solution in THF, persisted through dilution with up to 50 % of pre-cooled acetonitrile. For the THF/CH₃CN experiments, complex 23 was prepared in THF as illustrated in Figure 3 and held for 30 min at 40 °C before being diluted with cold (−45 °C) acetonitrile and subsequently cooled to the sampling temperature of −78 °C.

Cold electrospray of complex 23 results in several ions containing one and two palladium atoms (Figure 4), clearly distinguished by their broad isotopic pattern. Ions in this discussion are annotated by their most abundant monoisotopic masses, and composition of matter was confirmed for each assigned ion by matching the exact mass and observed isotopic pattern with simulated patterns. The most intense ion observed (m/z 713) matches the molecular formula [C₃₀H₅₈FP₂Pd₂]⁺ (calculated: 713.2080 found: 713.2078) which is consistent with the ionization of complex 23 by loss of a bromide ion. This bromide-loss ion (m/z 713) was also detected in pure THF indicating that a bromide-loss ionization pathway does not require the presence of a high-dielectric solvent. However, in pure THF total signal intensity was quite poor, and no bromide-retaining ions were detected, motivating the acquisition of all other spectra in a 1:3 mixture of MeCN and THF.

Figure 4.

Left, mass spectrum resulting from modified cold-spray ionization of complex 23 containing relevant species labeled above 10 % abundance. Proposed structures of the notable ions are shown in the middle, other assignments may be found in the Supporting Information. At far right are simulated peaks illustrating the distinctive multi-Pd isotopic pattern, and positive confirmation of the peak at m/z 791.1175 matching the molecular formula of complex 23, minus a hydride equivalent. Simulated peaks are modeled as Gaussian distributions at a resolution of 60000.

An additional, lower intensity ion centered at m/z 791.1156 matches the elemental composition [C₂₆H₄₉BrFP₂Pd₂]⁺ (calculated: 791.1177 found: 791.1156) which is consistent with the ionization of complex 23 by loss of a hydride ion. We propose such an ion may reasonably form during electrospray if the aryl ligand of 23 undergoes a C-H insertion to the adjacent Pd center, followed by hydride loss. The absence of an ion at m/z 791 in pure THF might be indicative of a solvent-dependent ionization pathway, or simply a consequence of the low ion counts observed in THF.

We believe this hydride elimination is a consequence of the high voltages applied in electrospray, and therefore dependent on a high-dielectric solvent. The total intensity of ions around m/z 791 could be improved with more suitable electrospray solvents, but ¹⁹F NMR experiments showed higher concentrations of acetonitrile reduced the stability of the desired complex. This ion critically establishes the closest composition of matter to the proposed neutral complex 23. The overlapping envelope centered at m/z 786.2244, remains unassigned despite our best efforts at characterization. The intensity of this overlapping peak was highly unstable between scans, and we suspect it is a product of mild degradation or rearrangement of 23 during electrospray. Other multi-Pd peaks, possibly indicative of solvent-mediated clusters, are observed in ESI-MS spectra, but none are sufficiently enlightening to be worthy of discussion.

The observation of ions with m/z 713 and m/z 791 in the cold electrospray ionization (CSI) experiments are consistent with the proposed structure of 23. To provide further information on the structure and gas-phase reactivity of these unusual binuclear Pd complexes, we utilized highenergy collisional dissociation (HCD)²⁶ tandem mass spectrometry to generate fragment ions in the gas-phase. In this technique, ions of interest are isolated in the C-trap of the Orbitrap XL mass spectrometer and accelerated into a dedicated octupole collision cell containing He bath gas. This MSⁿ technique has several advantages over more conventional collision-induced dissociation (CID) experiments carried out in LTQ mass spectrometers. Ion-selection in the C-trap is more precise and the lifetime of ions and collisional energies accessible in the octupole collision cell allow for both collisional dissociation and ion-molecule reactions that can provide rich information on the structure and reactivity of the selected ions. Further, the storage and transmission capacities of the C-trap are markedly higher than the LTQ, which proved critical in resolving the full isotopic pattern of multi-Pd ions.

Fragments resulting from HCD treatment of the bromide-loss ion centered at m/z 713.2078 are shown in Figure 5. The sequential loss of isobutene via a McLafferty-type rearrangement confirms the presence of tri-tert-butylphosphine in each of the fragments, while the isotopic patterns definitively match di-palladium species. Fragmentation by HCD of the putatively bromide-containing ion centered at 791.1177 results in several fragment ions matching those in Figure 5, corroborating the relationship between the two species. Annotated HCD spectra for both ions can be found in the Supporting Information. In addition to features that confirm structural motifs, most of the observed fragment ions retain a Pd-Pd bond. These rearrangements after the loss of the bromide and aryl motifs suggests a surprisingly robust Pd-Pd bond, apparently ambivalent in the gas phase to the presence of bridging ligands.

Figure 5.

Fragments detected by tandem MS (HCD) treatment of ions centered at m/z 713.2078 (isolation range of 15 m/z). Proposed formulas were matched to peaks by comparison of monoisotopic mass and isotopic pattern to simulated spectra.

Mass spectrometric data are consistent with the proposed structure of 23, in both composition of matter and connectivity. Repeated low-temp and air-free MS observation and corroboration by ¹⁹F NMR strongly support the structural assignment of the proposed binuclear aryl-palladium bromide complex. Furthermore, the HCD experiments suggest the presence of a robust palladium-palladium bond that remains intact even as the various ligands are stripped from palladium.

3.1.5. Transmetalation and Oxidative Addition Reactions with Complex 23.

With strong evidence supporting the structural characterization of 23, its reactivity was next explored. It was hypothesized that 23 could be competent to undergo both transmetalation, furnishing two palladium(0) complexes following reductive elimination, and oxidative addition, furnishing two equivalents of arylpalladium(II) halide.

To explore whether transmetalation occurs when boronate 19 is combined with complex 23, 1.0 equiv of oxidative addition complex 18 was combined with 1.0 equiv of boronate 19 in THF at −10 °C. After the reaction mixture was aged for 100 s at −10 °C, arylpalladium bromide complex 18 had reacted quantitatively with 0.5 equiv of boronate 19 to generate 0.5 equiv of complex 23 and 0.5 equiv of biaryl 20 (Figure 6). From this point, complex 23 and boronate 19 continued to react to form biaryl 20, albeit at a substantially reduced rate.

Figure 6.

Path A transmetalation at −10 °C, showing further transmetalation from complex 23.

Beginning with the timepoint at which the concentration of complex 23 is at a maximum, the stoichiometry of reaction was examined. For each equiv of boronate 19 consumed, one equiv of biaryl 20 is formed, suggesting quantitative conversion from boronate 19 to product 20. However, an excess of complex 23 is consumed in the process. Given the observed instability of 23 at −10 °C (Section 3.1.3), it is likely that the excess consumption of complex 23 is the result of concurrent decomposition of the complex.

Next, the propensity of complex 23 to react with an aryl halide in an oxidative addition reaction was explored. First, 10 μmol of arylpalladium bromide complex 18 was combined with 0.5 equiv of boronate 26 in THF at −78 °C, then warmed to −40 °C to generate 5 μmol of 23 with complete consumption of 18 and 26. The mixture was cooled to −78 °C, 5 μmol of aryl bromide 27 in THF were added to the solution of complex 23, the mixture was warmed to −10 °C and monitored by ¹⁹F NMR spectroscopy (Figure 7). The concentration of complex 23 and aryl bromide 27 decreased over time, and the concentration of oxidative addition complex 18 increased over time. Furthermore, a small amount of biaryl product 14 was observed to form (Figure 7).

Figure 7.

Conversion of complex 23 into oxidative addition complex 18 in the presence of aryl bromide 27.

Once again, the change in concentration of complex 23 and aryl bromide 27 was identical, suggesting the two are reacting with 1:1 stoichiometry. For each equiv of aryl bromide 27 and complex 23 that are consumed, 1.3 equiv of arylpalladium halide complex 18 are generated. Furthermore, biaryl 14 is generated in sub-stoichiometric quantities. The generation of biaryl 14 may be the result of decomposition of complex 23 or arylpalladium halide complex 18.

In summary, complex 23 undergoes transmetalation and subsequent reductive elimination to form biaryl 20 when combined with boronate 19 and undergoes oxidative addition when combined with aryl bromide 27 to form arylpalladium halide complex 18. Although neither reaction proceeds in quantitative yield, decomposition of the relevant palladium species is a plausible explanation for the remainder of the mass balance. Altogether, these observations establish the reactivity of the new complex and further support the structural hypothesis put forward in Section 3.1.3.

3.1.6. Exploration of Transmetalation through Path B and Path C.

Having established the kinetic competence of the boronate pathway, the investigation continued by exploring whether the oxo-palladium pathway was also potentially operative. By combining 4-F-C₆H₄Pd[P(t-Bu)₃]OTMS (21) with neopentyl 3,5-bistrifluoromethylphenylboronic ester (22) at −40 °C, the competence of the oxo-palladium pathway could be tested. However, multiple species exhibiting broad resonances were observed when TMSOK and 18 were mixed in a 1:1 ratio in d8-THF.²⁷ The collected data, discussed in the Supporting Information, suggest that 4-FC₆H₄Pd[P(t-Bu)₃]OTMS (21) may not exist as a well-defined compound at this concentration and temperature, and that it may be in an equilibrium with free TMSOK and other palladium complexes. Only upon addition of a 2^nd equivalent of TMSOK as a solution in d8-THF did the speciation re-converge, resulting in a new species exhibiting a ¹⁹F NMR resonance at −126 ppm (Scheme 8, see the Supporting Information for full characterization data).

Scheme 8.

Reaction Between 18 and 1 or 2 Equiv of TMSOK

Despite not having a well-defined method for the generation of 4-F-C₆H₄Pd[P(t-Bu)₃]OTMS (21), the reaction between putative complex 21 and neopentyl 3,5-bistrifluoromethylphenylboronic ester (22) was investigated (Scheme 9). First, 1.0 equiv of a THF solution of TMSOK was added to a THF solution of arylpalladium bromide complex 18 in a 5-mm NMR tube held at −78 °C. Next, a THF solution containing 1.0 equiv of neopentyl 3,5-bistrifluoromethylphenylboronic ester 22 was added at −78 °C, the mixture was inserted into an NMR magnet pre-cooled to −40 °C and the evolution of species over time was monitored by ¹⁹F NMR spectroscopy.

Scheme 9.

Experiment Designed to Probe Transmetalation Through the Oxo-Palladium Pathway.

At t = 0 s, the biaryl product 20 had already been formed at a concentration of ca. 4 mM, corresponding to a roughly 25% yield w.r.t. initial arylpalladium halide complex 18. Also present was 8-B-4 boronate 19, present in 8 mM concentration, alongside several species containing palladium, which are discussed in more detail in the Supporting Information. The system was monitored at −40 °C for 20 min, but no further change in concentration of 19 or 20 was observed.

These results are not compelling; determination of the reaction rate law (vide infra) ultimately furnished more conclusive evidence against transmetalation through the oxo-palladium pathway (path B). Nonetheless, several inferences can be made from these data. First, the oxo-palladium pathway may be very fast, given that biaryl product was formed prior to the acquisition of spectra at −40 °C. However, the inability to characterize arylpalladium-OTMS complex 21 as a discrete intermediate suggests that KOTMS may not displace bromide from the palladium complex. The generation of 8-B-4 boronate 19 from the mixture of putative arylpalladium silanolate complex 21 and 6-B-3 ester 22 further supports the notion that the binding affinity of TMSOK towards boronic ester 22 is much greater than its affinity towards palladium complex 18. The prior two observations, in concert with kinetic evidence refuting transmetalation through the oxo-palladium mechanism in this system (vide infra), suggest that even if the barrier to the reaction between 21 and 22 is low, the speciation in solution may render the oxo-palladium mechanism inoperative. An expanded discussion of the investigation into transmetalation through the oxo-palladium pathway is included in the Supporting Information.

Finally, an experiment was carried out to study transmetalation in the presence of excess TMSOK (Path C). First, 4-F-C₆H₄Pd[P(t-Bu)₃]Br (18) was mixed with 3.0 equiv of TMSOK in THF at −78 °C to generate a new complex as shown in Scheme 8. Next, a THF solution of 1.0 equiv of neopentyl ester 22 was added at −78 °C. The neopentyl ester rapidly reacted with TMSOK to form boronate 19 in situ. The reaction mixture containing 1.0 equiv 4-F-C₆H₄Pd[P(t-Bu)₃]OTMS (21), 1.0 equiv boronate 18, and 1.0 equiv TMSOK in THF was lowered into a NMR magnet pre-cooled to −40 °C, and the evolution of species over time was monitored using ¹⁹F NMR spectroscopy. No changes were observed over the course of 20 min. The magnet was warmed to −10 °C, and again monitored by ¹⁹F NMR spectroscopy, and no change was observed over the course of 20 min. Finally, the NMR magnet was warmed to 10 °C, at which temperature 28 decomposed without conversion to biaryl 20. Clearly the palladium complex formed in the presence of an excess of free TMSOK is not competent to undergo transmetalation with boronate 18. These data suggest the path C reaction mechanism is not viable, which is in good agreement with the dependence of reaction yield on base stoichiometry and prior results obtained by Amatore, Jutand, and Le Duc.¹⁴

3.1.7. Summary of Results from Stoichiometric Reactions.

In summary, formation of a putative pre-transmetalation intermediate through the boronate pathway (path A) is kinetically viable, and it leads to the generation of a heretofore unknown intermediate 23. The reactivity and structural characterization data of 23 are consistent with the structural hypothesis put forward in Section 3.1.3. Attempts to characterize arylpalladium silanolate complex 21 showed the generation of new species with the consumption of arylpalladium halide complex 18, but the lack of a single, discrete complex suggests that the binding between arylpalladium(II) and trimethylsilanolate is relatively weak compared to that between arylpalladium(II) and hydroxide. Experiments probing transmetalation through the oxo-palladium pathway (path B) were ultimately inconclusive. Finally, the lack of reactivity observed through path C offers an explanation for the relationship between base stoichiometry and reaction yield observed in the TMSOK-promoted Suzuki-Miyaura reaction. No new NMR resonances consistent with a Pd-O-B intermediate were observed, suggesting that if such an intermediate exists, it lies at the unfavorable end of an equilibrium, or exists on the reaction coordinate after the turnover-limiting step.

Next, a rate equation for the TMSOK-promoted Suzuki-Miyaura reaction of neopentyl boronic esters was determined to identify the species that are involved between the resting state and turnover-limiting transition state. Furthermore, such experiments could reveal whether complex 23 represented an artifact of the stoichiometric reaction conditions or a relevant catalytic intermediate.

3.2. Kinetic Analysis of the TMSOK-Promoted, Suzuki-Miyaura Reaction.

3.2.1. Experimental Design.

The inconclusive results for path B in the previously described studies under stoichiometric conditions precludes the direct comparison of transmetalation rates through path A and path B. Determination of the rate equation through kinetic analysis could provide compelling evidence for which pathway is operative in the catalytic reaction.

Even when electron deficient neopentyl 3,5-bistrifluoromethylphenylboronic ester (22) was used as the nucleophile with the intent to lower the reaction rate by decreasing the migratory aptitude of the migrating arene, the reaction was >50% complete in seconds at 22 °C. To allow for the collection of sufficient initial rate data for kinetic analysis, reactions were performed at −25 °C. Arylpalladium halide complex 18 (from 4-fluorobromobenzene) was chosen as the palladium source, as it is assumed to be a competent catalytic species that does not require activation to enter the catalytic cycle.²⁸ For the electrophilic species, 4-bromofluorobenzene was chosen because fluoroarenes have a substantial dependence of ¹⁹F chemical shift on electronic environment, allowing for the identification and quantification of species by ¹⁹F NMR spectroscopy.

Kinetics experiments were performed by pre-mixing THF solutions of boronic ester 22, aryl bromide 27, arylpalladium halide complex 18, and an internal standard in a 5-mm NMR tube, then adding a solution of TMSOK in THF at −78 °C, with the reaction initiated by lowering the tube into an NMR magnet pre-cooled to −25 °C. All experiments were performed in triplicate and error bars represent the standard deviation of the triplicate rates. Partial reaction orders were determined using the method of initial rates. The mixture was allowed to age for 100 s to establish a steady state, then the rate was measured as the slope of product formation vs. time for 11 time points between 100 and 200 s. All partial reaction orders were determined by fitting the power function y = k_obs[conc]^a, where y represents the initial rate, k_obs represents the observed rate constant, [conc] represents the concentration of reagent, and “a” represents the partial reaction order.

Because TMSOK reacts rapidly and completely with boronic ester 22 to form boronate 19, the concentration of free TMSOK in all reactions is negligible. The concentration of TMSOK in the reaction cannot be independently controlled - changing the amount of TMSOK added to the reaction only changes the concentration of boronate 19 and boronic ester 22. Free TMSOK in excess of boronic ester 22 severely inhibits the reaction (Section 3.1.6). As a result, the following kinetic investigation determines the reaction order for each major species in solution: aryl halide 27, boronate 19, boronic ester 22, and palladium catalyst 18.

3.2.2. Reaction Order in Aryl Halide 27.

First, the partial reaction order in aryl halide was determined (Figure 8). Across an 8-fold range of concentrations, the partial reaction order in aryl bromide was found to be 0.49 ± 0.02. A dependence of rate on aryl bromide concentration precludes turnover-limiting transmetalation through either the boronate or oxo-palladium pathway. Furthermore, the fractional reaction order is consistent with a mechanism wherein a reversible dissociation of one species into two occurs. The most likely candidate for such a species is 23, which could dissociate to give small equilibrium concentrations of arylpalladium halide 18 and monoligated palladium(0) complex 24 (Scheme 7).

Figure 8.

Plot of initial rate vs. the concentration of aryl bromide 27.

Having established the surprising presence of oxidative addition in the rate equation, we continued to establish partial reaction orders for the other reaction components.

3.2.3. Reaction Order in Boronate 19.

Next, the partial reaction order in boronate 19 was determined. The partial reaction order with respect to boronate 19 was observed to be 0.89 ± 0.14 (Figure 9). Furthermore, the partial reaction order with respect to boronate 19 was observed to be 0.98 when the experiment was repeated with [27]₀ = 1.0 instead of 0.25 M (Supporting Information, page S69).

Figure 9.

Plot of initial rate vs. the concentration of boronate 19.

The experimentally determined partial reaction order of 0.89 ± 0.14 is close to unity, and we assume a 1^st order rate dependence on the concentration of 19. Other models can be created to fit the observed data - it is possible that the reaction order of 0.89 represents the partial saturation of an equilibrium giving rise to a fractional reaction order, or multiple simultaneous mechanisms. Furthermore, the data appear to have a slight upward trend. Two simultaneous reactions, one 0th-order in 19, and another 2^nd order in 19, could result in a parabolic rate dependence with a non-zero y-intercept. However, no chemically reasonable hypothesis was imagined as to why such a rate law would be observed. Therefore, it is most appropriate to assume roughly 1^st order behavior in boronate 19.

3.2.4. Reaction Order in 6-B-3 Boronic Ester.

When the initial rate was measured across a 4-fold range in concentration of boronic ester 22, no deviations in the rate were observed (Figure 10). Fitting the data to the power function y = k_obs[22]^a reveals that the partial reaction order with respect to 6-B-3 boronic ester 22 is zero.

Figure 10.

Plot of initial rate vs. the concentration of boronic ester 22.

A 0^th-order dependence on the concentration of boronic ester 22 provides strong evidence against an oxo-palladium (path B) mechanism. In a path B mechanism, 6-B-3 boronic ester 22 plays two roles, one beneficial and one antagonistic. It is implicated in the transmetalation step, reacting with an arylpalladium-oxyanion complex, but also sequesters the base required to generate an arylpalladium-oxyanion complex. Amatore, Jutand, and Le Duc demonstrate that this dichotomy causes the reaction order in boron species to depend on the concentration of those boron species.¹⁴ However, in Amatore, Jutand, and Le Duc’s studies, the reaction order in boronic acid is non-zero at all concentrations of boronic acid. Given the high affinity of TMSOK for boronic esters, the comparatively low affinity of TMSOK for Pd complexes (Section 3.1.6), the 0^th-order partial reaction order in 6-B-3 ester 22, and the 1^st order rate dependence on boronate 19, it is not unreasonable to conclude that transmetalation occurs through a reaction between arylpalladium bromide complex 18 and boronate 19 (path A).

To complete the mechanistic picture, the reaction order in arylpalladium bromide complex 18 was determined.

3.2.5. Reaction Order in Arylpalladium Halide Complex 18.

Over an 8-fold range of catalyst concentrations, the reaction order in arylpalladium halide was determined to be 0.55 ± 0.06 (Figure 11).

Figure 11.

Plot of initial rate vs. the concentration of arylpalladium halide 18.

The observation of a half-order rate dependence on the catalyst concentration is also consistent with a mechanism wherein catalyst disproportionation occurs between the resting state and the turnover limiting step, in agreement with the partial reaction order in aryl halide 27.

3.2.6. Summary and Discussion of Kinetic Results.

Overall, the kinetic investigations revealed that the reaction is half-order in arylpalladium bromide complex 18, half-order in aryl bromide 27, roughly first-order in 8-B-4 complex 19, and 0^th-order in 6-B-3 boronic ester 22 resulting in the following rate equation:

$$\frac{d\left[\mathbf{20}\right]}{dt}=k_{obs}{[\mathbf{18}]}^{0.55}{[\mathbf{27}]}^{0.49}{[\mathbf{19}]}^{0.89}$$ (1)

The fractional partial reaction order with respect to 18 and 27 indicates a complex reaction mechanism involving at least one equilibrium. A half-order rate dependence suggests reversible dissociation of one species into two – the most likely species to fill that role is binuclear complex 23, particularly given that it is observed in the reaction mixture by ¹⁹F NMR spectroscopy (Supporting Information page S21). Four potential mechanisms involving reversible reactions of 23 were considered for the catalytic reaction (Scheme 10). A rate law was derived for each to determine whether the mechanism in question can account for the observed reaction orders. In each of the derivations, there exists a critical bifurcation wherein the rate law depends on the resting state speciation in solution. In general, if the catalytic resting state has at least a moderate concentration of 23, the reaction will exhibit a half-order rate dependence on one or more of the species in solution. If, instead, the resting state palladium species is a mononuclear complex, no fractional reaction orders are observed. A more detailed explanation of this conclusion and a full examination of each rate law are provided in the Supporting Information (pages S110–S130).

Scheme 10.

Four Mechanisms that were Considered for the Catalytic Reaction.

The first mechanism (mechanism I) involves reversible oxidative addition of aryl bromide 27 into binuclear complex 23. The reversibility of oxidative addition in tri-tert-butylphosphine ligated palladium complexes has been previously demonstrated by Hartwig and co-workers.²⁹ The reaction orders predicted for mechanism I depend on the position of the equilibrium 23 + 27 ⇌ 2x 18. A rate law of [18]^0.5 [27]^0.5 [19]¹ is predicted if the oxidative addition equilibrium favors 23 + 27, and a rate law of [18]¹ [27]⁰ [19]¹ is predicted if the equilibrium favors 18. The experiments performed herein demonstrate that if such an equilibrium is accessible in our system, it must favor 18. Arylpalladium bromide complex 18 is observed to be stable in solution and does not spontaneously release aryl halide to form binuclear complex 23. Furthermore, when 23 and 27 were combined, arylpalladium bromide complex 18 was formed (Section 3.1.5). Because mechanism I requires an equilibrium that favors 23 and 27 to give rise to the experimentally observed reaction orders, it can be ruled out.

The next mechanism considered (II) involves reversible and unfavorable dissociation of 23 into arylpalladium bromide complex 18 and L₁Pd(0) complex 24. Given that the catalyst resting state contains 23, the reaction rate would be proportional to [18]^0.5 [27]^0.5 [19]^0.5 - mechanism II does not result in a rate law of [18]^0.5 [27]^0.5 [19]^1.0 under any circumstances. The half-order rate dependance on 27 and 19 arises because oxidative addition and transmetalation each turn over 23, but also creates a species that drives the equilibrium 18 + 24 ⇌ 23 to the right.

A rate law of [18]^0.5 [27]^0.5 [19]¹ can be observed when there are two distinct pathways by which boronate 19 drives the equilibrium 18 + 24 ⇌ 23 to the left. In one such proposed mechanism (III), alongside consuming 18 through transmetalation, boronate complex 19 reversibly binds L₁Pd(0) complex 24 in solution. So long as the resultant complex is still competent to undergo oxidative addition, a reaction rate law of [18]^0.5 [27]^0.5 [19]¹ is possible. Given the coordinatively unsaturated nature of the 12 e⁻ L₁Pd(0) complex 24, it is not unreasonable to propose that 24 would bind to 19 to form a new complex.

The data presented herein are consistent with the proposed catalytic cycle shown in Figure 12. However, alternative mechanisms whereby boronate complex 19 turns over binuclear palladium complex 23 through two distinct pathways are possible. For example, mechanism IV, wherein boronate complex 19 is implicated in the breakup of the binuclear complex as well as in the transmetalation step, could exhibit a rate law of [18]^0.5 [27]^0.5 [19]¹. The kinetic and stoichiometric data presented herein cannot differentiate between mechanisms III and IV. Furthermore, the proposed complex incorporating 19 and 24 has not been observed or characterized – as such, alternate proposed mechanisms that match all gathered data but do not include 19•24 would be equally valid.

Figure 12.

Proposed catalytic cycle for TMSOK-mediated, Suzuki-Miyaura cross-coupling reaction.

Altogether, the lack of observed rate dependence on the concentration of 6-B-3 boronic ester 22, the positive rate dependence on the concentration of boronate complex 19, and the observations from studies carried out under stoichiometric conditions strongly support the conclusion that transmetalation takes place through path A, the boronate pathway. The observation of binuclear palladium complex 23 in the reaction mixture by NMR spectroscopy, alongside the half-order dependence in arylpalladium complex 18 and aryl bromide 27, demonstrate that binuclear palladium complex 23 is more than a curiosity - it is an important intermediate relevant to the catalytic cycle.

Although the use of neopentyl boronic esters as the transmetalating partner and TMSOK as the base differs from “standard” Suzuki-Miyaura reaction conditions, these differences largely affect the transmetalation step. Because transmetalation is not involved in the proposed reaction between P(t-Bu)₃Pd(0) and ArylPd[P(t-Bu)₃]Br to form dinuclear palladium complex 23, it could take place in a significant number of systems. The fundamental difference then, may be that very few Suzuki-Miyaura reactions are conducted at −25 °C. With the extraordinary rate of transmetalation observed in this system, the assumption of transmetalation as a turnover-limiting step breaks down, and steps that were previously kinetically silent may become significant.

3.3. Computational Investigation of Binuclear Pd complex 23.

3.3.1. Introduction.

The discovery of binuclear Pd complex 23 as a catalytic intermediate was surprising. Although many binuclear Pd(I) complexes are known³⁰, no binuclear Pd(I) complex containing a bridging aryl ligand analogous to 23 has been characterized. The only literature precedent is the unligated, binuclear Pd(I) complex 29, described by Aleksandrov et al. in a computational study of Pd nanoparticle leaching.³¹

Although no μ-phenyl bridged binuclear palladium(I) complex has been experimentally characterized, a limited number of μ-phenyl bridged binuclear palladium(II) complexes have been characterized, with structures confirmed by X-ray crystallography (Figure 13). The majority of research on μ-phenyl bridged palladium complexes has focused on the study of 30 through the lens of fundamental inorganic/organometallic chemistry.³² Analogous complexes such as 31 have been prepared to elucidate when Pd(II) μ-phenyl dimers are stable.³³ Binuclear complex 32 was isolated as an intermediate in the cross-coupling reaction between aryl halides and triarylstibanes.³⁴ Likewise, binuclear Pd(II) complex 33 was computationally implicated as an intermediate in the Catellani reaction.³⁵ Finally, binuclear Pd(II) complexes with μ-phenyl bridging ligands have been implicated in the mechanism of Pd-mediated domino reactions,³⁶ and stoichiometric reactions with organotin reagents.³⁷ Although they are analogous, these Pd(II) binuclear complexes exhibit markedly different reactivity from binuclear Pd(I) complex 23.

Figure 13.

Selected examples of previously described binuclear Pd(II) complexes containing μ-phenyl ligands.

From the literature survey summarized above, it appears that complexes analogous to 23 are thus far unknown. The novelty of complex 23 prompted us to undertake a computational investigation of its structure and bonding. Of particular interest is the geometry about the 4-fluorophenyl ligand, which could conceivably be either a μ-phenyl bridging ligand, or a σ-phenyl ligand bound to one palladium center with η¹-coordination to the other palladium center. If the equilibrium geometry were found to contain a σ-phenyl ligand, the complex would need to undergo rapid interconversion to explain the symmetry deduced from the ¹H and ³¹P NMR spectra. Finally, the persistence of a Pd–C–Pd unit in the MS fragmentation led to an investigation into Pd–Pd bonding interactions in the complex.

3.3.2. Computational Studies.

In order to facilitate the computational investigation of complex 23 preliminary studies were performed on the model complex 34, wherein the tri-tert-butylphosphine ligands were replaced with trimethylphosphine analogs, and the 4-fluorophenyl substituent was replaced with phenyl for the sake of faster computing time. Calculations were carried out in ORCA 4.2.1 release version.³⁸ Optimization of the model structure in the singlet state at RPBE³⁹ / def2-TZVP + ECP(Pd) level of theory showed a strong preference for the unsymmetrical structure 35 with the geometry depicted in Figure 14. The structure did not possess a local C_s symmetry that was anticipated given the experimental NMR chemical shift equivalency of both phosphorus nuclei. The μ²-aryl group was tilted away from the bisecting plane of Pd-Br-Pd angle (angle Br-C(1)-C(4): 150.3°). The structure obtained at this level of theory can be rationalized chemically as an LPd(0) species utilizing C(1) atom of the LPd(II)(Aryl, Br) oxidative addition fragment as a ligand. When attempts were made to constrain several internal coordinates so that the geometry would resemble the anticipated symmetric structure, a few imaginary modes were obtained, and, upon inspection, one with phenyl group wagging was identified. Uphill eigenvector following yielded a symmetrical transition state 36 which again displayed several unexpected geometric features. First, the Br-Pd-C(1)-Pd fragment was significantly puckered, as opposed to being flat, as seen in previously characterized LPd(I)Br dimers (see complexes 37 and 38 in the Supporting information). Second, the Pd—Pd contact elongated by 0.04 Å in transition state, as compared to equilibrium structure, potentially indicating a disfavored and avoided Pd—Pd close contact. These observations strongly contradicted the hypothesis of a strong Pd—Pd bonding interaction.

Figure 14.

Geometries of computational models and the corresponding electronic structures.

We hypothesized that utilization of restricted Kohn-Sham DFT theory may be inappropriate for this complex owing to its inability to correctly describe multireference wavefunctions and decided to obtain a more rigorous picture from a multi-reference method.⁴⁰ Calculations performed at the SA-CASSCF(2,2)⁴¹ / def2-TZVPPD⁴² level of theory indicated that both structures 35 and 36 possessed a significant multireference character. Even more surprising, the predicted ground electronic state was open shell with a ca. 0.1 eV triplet-singlet splitting in the transition state. These results suggest that the ground state multiplicity and/or the type of reference wavefunction were misidentified in the prior calculations. This hypothesis is supported by the propensity of the multireference solution to converge to states with significant open-shell character. As a result, an optimal geometry was calculated with UPBE / def2-TZVP + ECP(Pd) in the high spin (triplet) state. Beginning with the transition state geometry 36, the calculation quickly converged on a symmetric structure 39-T which had not been observed before. Analytical frequency calculation confirmed that the new structure 39-T represented a true minimum on the potential energy surface. Attempts to obtain an unrestricted wavefunction for a singlet electronic state were unsuccessful due to numerical instability.

Application of SA-CASSCF(2,2) / def2-TZVPPD method to structure 39-T established that the structure now matched the objective of the DFT optimization: all states were singledeterminantal, with the lowest one corresponding to the open-shell triplet state. The symmetry of the structure matched the one deduced from the NMR experiments. Additionally, this epiphany allowed us to rationalize the major mismatch of the structures obtained within RKS and UKS formalism. The effect likely arises from the presence of doubly degenerate, singly occupied nonbonding d-orbitals. Restricted Kohn-Sham orbitals necessitate the double occupancy of one of the two degenerate orbitals, causing a Jahn-Teller effect to emerge. Removal of the orbital degeneracy is possible through a geometry distortion, which results in heavily distorted structures in both the equilibrium and transition state. We believe that both symmetric and distorted geometries are in agreement with each other, once the consequences of orbital degeneracy are taken into account. Optimization of the complex 40 at the UKS-DFT level of theory delivered the same symmetric structure. This observation demonstrates that the structural features are general and should be attributed to the electronic structure of the complex, not steric differences between complexes 34 and 40.

Apart from geometric parameters, the other notable feature of 39-T is the absence of direct two-center metallic bonding, as evidenced by the Mayer bond order of 0.22 at the DKH2-FN/UPBE/aug-cc-PVTZ-DK level of theory. An alternative possibility for bonding is a three-center four-electron bond. The lowest energy bonding orbital of this sort is presented in Figure 15a. Analogous explanations for the absence of direct metallic bonding have previously been made for other binuclear palladium complexes.^41,43 We propose that the emergence of this three-centered bond with the μ²-aryl group, the disappearance of a two-center metallic dσ bond, and the appearance of the nonbonding unpaired electrons are a result of the strong σ-donor and weak π-acceptor properties of an aryl group. A plausible orbital overlap that could be responsible for this outcome is depicted in Figure 15b. Broken-symmetry DFT calculations were performed to estimate the energy of 39-S. The calculations support a ferromagnetic coupling between the unpaired electrons, which results in preference for the high-spin (triplet) configuration. The value of magnetic coupling constant (see the Supporting Information) does not appear to be strongly dependent on the percentage of exact exchange, as hybrid functionals produce similar results to pure GGA or meta-GGA functionals. Given that 23 exhibits sharp NMR resonances with unremarkable chemical shift values, we favor the open shell singlet structure of 39-S as the tentative assignment of the ground electronic structure. It should be noted that the DFT electronic energies of species 35, 36, 39-S and 39-T do not align with our conclusions. According to DKH2-PBE calculations, the most stable structure is 35, followed by 36 (+72.0 kJ mol⁻¹), 39-T (+83.9 kJ mol⁻¹) and 39-S (+88.0 kJ mol⁻¹). This disagreement may be explained by improper treatment of multireference structure within a single-reference DFT formalism. This hypothesis is supported by the CASSCF energies. By comparing the ground electronic state energies, one can see that 39-T is the lowest energy species, followed by 39-S (+12.0 kJ mol⁻¹), 35 (+14.5 kJ mol⁻¹) and 36 (+55 kJ mol⁻¹). We cautiously favor the latter energies on the basis of more consistent electronic structure description, but we refrain from claiming our CASSCF calculations as conclusive in view of small active space and the absence of dynamic electron correlation.

Figure 15.

(A) Computed CASSCF orbital energies and occupancies, and the corresponding electronic states. (B) Proposed orbital overlap model to account for open shell d⁹-d⁹ structure in 39

Although the computational evidence suggests no Pd–Pd bond is present in 23, a dinuclear palladium species persists following fragmentation in the HCD-MS experiments, suggesting a Pd–Pd bond might be formed following fragmentation. To investigate further, the same analysis was performed on the cation 41, a simplified analog of the key molecular ion in the mass-spectrometric analysis (Figure 16). The optimized structure featured the same open shell ground state as its parent 39. Unlike the parent structure, cation 41-T featured a Pd–Pd bond (Mayer bond order of 0.73, DKH2-FN/UPBE/aug-cc-PVTZ-DK). The mass spectrometry data suggests the metallic bond persists throughout the series of subsequent fragmentations in the mass-spectrometer.

Figure 16.

Electronic structure of cation 41, its geometry and selected orbitals responsible for Pd–Pd and Pd–C–Pd bonding.

4. DISCUSSION

4.1. Dinuclear Palladium(I) Complex 23.

Given the extent to which oxidative addition has been studied, the discovery of a new, related complex is unexpected. The most obvious explanation why such a complex has not been identified is the elevated temperatures generally employed when studying oxidative addition, which may cause rapid decomposition of 23 analogues (Scheme 11a).⁴⁴ It is worth noting that oxidative addition to 23 is only slow relative to the rapid transmetalation reaction of TMSOK boronates. If other steps in the catalytic cycle are slow (i.e., in reactions requiring elevated temperatures to proceed at an appreciable rate), other steps may become turnover limiting, with steps involving 23-like species becoming kinetically silent.

Scheme 11.

Analogous Literature Examples in Which Analogs of 23 Were Not Formed, with Proposed Features that Lead to The Absence of 23 Analogs.

Another explanation for the absence is the instability of monoligated palladium(0) complexes. Although monoligated palladium(0) complexes are frequently implicated as reaction intermediates through kinetic studies, the reactivity of such complexes has thus far precluded their direct spectroscopic characterization. In general, complexes stabilized by additional phosphine ligands or ligands such as dibenzylideneacetone (dba) are used as precursors to a monoligated palladium(0) complex. Even when conducted at low (0 °C – 30 °C) temperature, no analog of 23 is observed during oxidative addition reactions of bisligated palladium species (Scheme 11b).^43,45

It appears the presence of additional ligands precludes the formation of complexes analogous to 23. The inability of ArylPd(Pt-Bu₃)Br to dimerize, in contrast with arylpalladium compounds bearing other phosphine ligands, may also play a role. Likewise, other transmetalation reactions of 18 and analogous complexes fail to generate analogs of 23. It is also hypothesized that the formation of new complexes such as silanolate complex 47 (Scheme 11c) or μ-hydroxide palladium dimer 11 (Scheme 11d) prior to transmetalation precludes the formation of 23 analogues.^46,19

Complexes analogous to 23 may be relevant intermediates in reactions other than the TMSOK-promoted Suzuki-Miyaura reaction. Pre-catalysts that generate monoligated palladium(0) species are very useful for palladium-mediated reactions. Because TMSOK and boronic esters are not implicated in the proposed mechanism of formation for 23, such a complex could be formed in other palladium-mediated reactions of aryl halides starting from monoligated palladium sources, particularly if an arylpalladium halide complex is proposed as the resting state. To summarize, intermediates such as 23 may not always form in Pd-mediated reactions of aryl halides, but should be considered when proposing a mechanism for reactions of aryl halides mediated by monoligated palladium(0) in the absence of supporting ligands.

4.2. The Lack of Reactivity Through Path C.

The lack of reactivity through path C can be interpreted in the context of productive reactivity through the boronate pathway or the oxo-palladium pathway. Given our conclusion that the boronate pathway is operative, the lack of reactivity suggests that boronate can displace a halide anion from an arylpalladium(II) complex, but cannot displace the silanolate ligand, particularly when it is present in excess which disfavors dissociation of TMSO⁻ through Le Chatelier’s principle. The potential binding of a second molecule of TMSOK to complex 21 (Scheme 6) to form a 10-electron, 5-coordinate silicon complex (10-Si-5) would further inhibit dissociation of TMSO⁻. If the oxo-palladium pathway were operative, the lack of free boronic ester that is not bound as the boronate would prevent reactivity, as was described by Amatore, Jutand, and Le Duc.¹⁴ It is notable that similar reaction stalling is observed when potassium tert-amylate is used as a homogeneous base in these reactions (Supporting Information, page S12), and analogous effects have been reported in other publications.⁴⁷ It follows that, in general, when a homogeneous, anhydrous Suzuki-Miyaura reaction is conducted in the presence of excess base, the reaction may be significantly inhibited by saturation of both the palladium complex and boron reagent with base.

4.3. The Unusual Boronate Transmetalation Mechanism.

In view of the longstanding assumption that the oxo-palladium (path B) mechanism is highly preferred for access to the pre-transmetalation intermediate, some comment on the demonstration that the boronate pathway (path A) dominates in this process is warranted. In support of the oxo-palladium pathway, Hartwig and Carrow demonstrated that transmetalation from potassium triolboronates is very slow at −40 °C. In contrast, the rate of transmetalation from TMSOK-ligated boronic esters is rapid at −40 °C. Furthermore, previous studies conducted by Amatore, Jutand, and Le Duc demonstrate that reactivity through the oxo-palladium pathway dominates when organic phase-soluble tetrabutylammonium boronates are used as the transmetalating partner.

We hypothesize that in this system, the viability of boronate transmetalation pathway (path A) from TMSOK-complexes of boronic esters is related to the solubility of the potassium boronate and the insolubility of the inorganic salt byproduct, KBr. The solubilized potassium cation could bind as a Lewis acid to the bromide in complexes such as 18, activating the arylpalladium bromide complex to transmetalation.⁴⁸ The tetrabutylammonium cation used in the Amatore/Jutand/Le Duc system would not have the same effect.⁴⁹ Likewise, Hartwig and Carrow’s use of 18-crown-6 to solubilize potassium boronate salts would inhibit the efficacy of potassium as a Lewis acid.

A possible explanation for a lack of reactivity through the oxo-palladium pathway observed herein is that the high affinity of TMSOK for boron and low affinity for palladium prevents the appropriate speciation to enable that pathway. The observation that ArylPdOTMS complex 21 is poorly defined when generated from a 1:1 mixture of arylpalladium bromide complex 18 and TMSOK supports this hypothesis. Alternatively, an oxo-palladium mechanism would be inhibited if TMSOK cannot effectively serve as bridging ligand between boron and palladium. An oxo-palladium mechanism would require initial formation of a Pd-O-B linkage through the -OTMS oxygen, as neopentyl glycol is bound to boron and not free in solution (Scheme 12a). In contrast, reaction through the boronate pathway allows the more nucleophilic oxygen of neopentyl glycol to act as the bridging ligand (Scheme 12b).

Scheme 12.

Implications of the Poor Bridging Ability of -OTMS on the Propensity to React Through the Oxo-Palladium and Boronate Mechanisms.

5. CONCLUSION

The mechanism of the TMSOK-promoted, anhydrous Suzuki-Miyaura cross-coupling reaction has been elucidated through kinetic analysis and the study of reactivity of isolated reaction intermediates. Stoichiometric studies show that in contrast to prior results, transmetalation through the boronate pathway (path A) can proceed quickly under appropriate reaction conditions. Furthermore, it was demonstrated that saturation of both palladium and boronate with base (Path C) precludes transmetalation, giving rise to base inhibition in homogeneous, anhydrous Suzuki-Miyaura reactions. During the course of the investigation, a novel, binuclear palladium complex containing an μ-arene ligand 23 was characterized and implicated as a catalytic intermediate. Investigation by DFT has demonstrated that the complex 23 is an unexpected open shell d⁹-d⁹ structure that is bound by three-centered four-electron bonds Pd–Br–Pd and Pd–C(1)–Pd. Finally, kinetic analysis supports the conclusion that transmetalation in the catalytic reaction proceeds through the boronate pathway (path A), and implicates 23 in the catalytic reaction mechanism. The findings described herein demonstrate an alternative manifold for the mechanism of the Suzuki-Miyaura cross-coupling reaction under different reaction conditions. The characterization of 23 has mechanistic implications for any reaction of aryl halides catalyzed by a monoligated palladium complex, particularly when an arylpalladium halide complex is proposed as the resting state.