Reaction solvent was previously shown to influence the selectivity of Pd/P
tBu
3-catalyzed Suzuki–Miyaura cross-couplings of chloroaryl triflates. The role of solvents has been hypothesized to relate to their polarity, whereby polar solvents stabilize anionic transition states involving [Pd(P
tBu
3)(X)]
− (X = anionic ligand) and nonpolar solvents do not. However, here we report detailed studies that reveal a more complicated mechanistic picture. In particular, these results suggest that the selectivity change observed in certain solvents is primarily due to solvent coordination to palladium. Polar coordinating and polar noncoordinating solvents lead to dramatically different selectivity. In coordinating solvents, preferential reaction at triflate is likely catalyzed by Pd(P
tBu
3)(solv), whereas noncoordinating solvents lead to reaction at chloride through monoligated Pd(P
tBu
3). The role of solvent coordination is supported by stoichiometric oxidative addition experiments, density functional theory (DFT) calculations, and catalytic cross-coupling studies. Additional results suggest that anionic [Pd(P
tBu
3)(X)]
− is also relevant to triflate selectivity in certain scenarios, particularly when halide anions are available in high concentrations.In the presence of the bulky monophosphine P
tBu
3, palladium usually prefers to react with Ar–Cl over Ar–OTf bonds. However, strongly coordinating solvents can bind to palladium, inducing a reversal of selectivity.
Oxidative addition is a key elementary step in diverse transformations catalyzed by transition metals.
1 For instance, this step is common to traditional cross-coupling reactions, which are among the most widely used methods for small molecule synthesis. During the oxidative addition step of cross-coupling reactions, a low valent metal [usually Pd(0)] inserts into a C–X bond with concomitant oxidation of the metal by two electrons. The “X” group of the C–X bond is commonly a halogen or triflate. Despite a wealth of research into this step,
2–5 uncertainties remain about its mechanistic nuances. The mechanistic details are especially pertinent to issues of selectivity that arise when substrates contain more than one potentially reactive C–X bond.
6One of the best-studied examples of divergent selectivity at the oxidative addition step is the case of Pd-catalyzed Suzuki couplings of chloroaryl triflates. In 2000, Fu reported that a combination of Pd(0) and P
tBu
3 in tetrahydrofuran (THF) effects selective coupling of 1 with
o-tolylB(OH)
2via C–Cl cleavage, resulting in retention of the triflate substituent in the final product 2a ().
7 In contrast, the use of PCy
3 (ref.
7) or most other phosphines
8 provides complementary selectivity (product 2b) under similar conditions. The unique selectivity imparted by P
tBu
3 was later attributed to this ligand''s ability to promote a monoligated oxidative addition transition state on account of its bulkiness.
5,8 Smaller ligands, on the other hand, favor bisligated palladium, which prefers to react at triflate. The relationship between palladium''s ligation state and chemoselectivity has been rationalized by Schoenebeck and Houk through a distortion/interaction analysis.
5 In brief, the selectivity preference of PdL
2 is dominated by a strong interaction between the electron-rich Pd and the more electrophilic site (C–OTf). On the other hand, PdL is less electron-rich and its selectivity preference mainly relates to minimizing unfavorable distortion energy by reacting at the more easily-distorted C–Cl bond.
Open in a separate windowSeminal reports on the effects of (A) ligands and (B) solvents on the selectivity of cross-coupling of a chloroaryl triflate.
5,7,9Proutiere and Schoenebeck later discovered that replacing THF with dimethylformamide (DMF, , entry 1) or acetonitrile caused a change in selectivity for the Pd/P
tBu
3 system.
9,10 In these two polar solvents, preferential reaction at triflate was observed, and P
tBu
3 no longer displayed its unique chloride selectivity. The possibility of solvent coordination to Pd was considered, as bisligated Pd(P
tBu
3)(solv) would be expected to favor reaction at triflate. However, solvent coordination was ruled out on the basis of two intriguing studies. First, DFT calculations using the functional B3LYP suggested that solvent-coordinated transition states are prohibitively high in free energy (about 16 kcal mol
−1 higher than the lowest-energy monoligated transition structure). Second, the same solvent effect was not observed in a Pd/P
tBu
3-catalyzed base-free Stille coupling in DMF (, entry 2). Instead, the Stille coupling was reported to favor reaction at chloride despite the use of a polar solvent. This result appears inconsistent with the possibility that solvent coordination induces triflate-selectivity, as coordination of DMF to Pd should be possible in both the Stille and Suzuki conditions, if it happens at all. Instead, it was proposed that the key difference between the Suzuki and Stille conditions was the absence of coordinating anions in the latter (unlike traditional Suzuki couplings, Stille couplings do not necessarily require basic additives such as KF to promote transmetalation). Indeed, when KF or CsF was added to the Stille reaction in DMF, selectivity shifted to favor reaction at triflate (, entry 3), thereby displaying the same behavior as the Suzuki coupling in this solvent. On the basis of this and the DFT studies, it was proposed that polar solvents induce a switch in chemoselectivity if coordinating anions like fluoride are available by stabilizing anionic bisligated transition structures (, right).However, our recent extended solvent effect studies produced confounding results.
11 In a Pd/P
tBu
3-catalyzed Suzuki cross-coupling of chloroaryl triflate 1, we observed no correlation between solvent polarity and chemoselectivity (). Although some polar solvents such as MeCN, DMF, and dimethylsulfoxide (DMSO) favor reaction at triflate, a number of other polar solvents provide the same results as nonpolar solvents by favoring reaction at chloride. For example, cross-coupling primarily takes place through C–Cl cleavage when the reaction is conducted in highly polar solvents like methanol, water, acetone, and propylene carbonate. In fact, the only solvents that promote reaction at triflate are ones that are commonly thought of as “coordinating” in the context of late transition metal chemistry.
12 These are solvents containing nitrogen, sulfur, or electron-rich oxygen lone pairs (nitriles, DMSO, and amides). The observed solvent effects were upheld for a variety of chloroaryl triflates and aryl boronic acids.
11Open in a separate windowExpanded solvent effect studies in the Pd/P
tBu
3-catalyzed Suzuki coupling.
11We have sought to reconcile these observations with the earlier evidence
9 against solvent coordination. Herein we report detailed mechanistic studies indicating that coordinating solvents alone are sufficient to induce the observed selectivity switch. In solvents like DMF and MeCN, stoichiometric oxidative addition is favored at C–OTf even in the absence of anionic additives. The apparent contradiction between our observations and the previously-reported DFT calculations and base-free Stille couplings is reconciled by a reevaluation of those studies. In particular, when dispersion is considered in DFT calculations, neutral solvent-coordinated transition structures involving Pd(P
tBu
3)(solv) become energetically feasible. Furthermore, we find that the selectivity analysis in the Stille couplings is convoluted by low yields, the formation of side products, and temperature effects. When these factors are disentangled, the Stille coupling in DMF displays selectivity similar to the Suzuki coupling in the same coordinating solvent. In light of these new results, anionic bisligated [Pd(P
tBu
3)(X)]
− does not appear to be the dominant active catalyst in nonpolar or polar solvents unless special measures are taken to increase the concentration of free halide, such as adding tetraalkylammonium halide salts or crown ethers.
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