Oxidation of a Cyclometalated Pd(II) Dimer with “CF₃⁺”: Formation and Reactivity of a Catalytically Competent Monomeric Pd(IV) Aquo Complex

Abstract

The reaction of [(bzq)Pd(OAc)]₂ (bzq = benzo[h]quinoline) with “CF₃⁺” reagents to afford the monomeric Pd^IV aquo complex (bzq)Pd(CF₃)(OAc)₂(OH₂) is demonstrated. Heating this Pd^IV adduct at 60 °C for 12 h leads to highly chemoselective Aryl–CF₃ bond-forming reductive elimination. The rate and yield of this transformation are both significantly enhanced by the addition of Brønsted and Lewis acidic additives. The mechanism of C–CF₃ bond-formation from (bzq)Pd(CF₃)(OAc)₂(OH₂) has been studied, and the major pathway is proposed to involve pre-equilibrium acetate dissociation followed by C–CF₃ coupling. Finally, this monomeric Pd^IV complex is shown to be a kinetically competent intermediate for C–H trifluoromethylation with “CF₃⁺” reagents. Collectively, these studies provide valuable insights about the speciation, nuclearity, and reactivity of Pd intermediates in catalytic C–H trifluoromethylation reactions.

Introduction

Over the past 6 years, the field of Pd-catalyzed ligand-directed C–H functionalization has grown exponentially.¹ Much of the work in this area has focused on using Pd catalysts in conjunction with strong oxidants (e.g., hypervalent iodine reagents, electrophilic halogenating reagents) to convert C–H bonds into C–C or C–heteroatom linkages.¹ Despite great progress in new reaction development, the nature of the catalytically active high oxidation state Pd intermediates in these transformations remains the subject of intense study and discussion.^2,3 For example, monomeric,^4,5 dimeric,^6,7 and trimeric⁸ Pd complexes in oxidation states ranging from +2 to +4 have all been proposed as catalytically active species.² Furthermore, while co-solvents and additives are frequently employed to promote these transformations, their effects are generally empirically derived and poorly understood.^1,2 Studies that provide further mechanistic insights should facilitate the optimization and rational design of new reactions in this area.

Several recent reports have focused on the role of cyclometallated Pd^II dimers like 1 and 3 (eqs 1 and 2) as intermediates in Pd-catalyzed C–H functionalization.^6,7 For example, the oxidation of 1 to generate acetate-bridged Pd dimer 2 has been kinetically implicated as the turnover-limiting step in C–H arylation reactions (eq. 1).⁶ Similar dimeric Pd^III adducts (4) have been isolated from the stoichiometric reaction of complex 3 (and analogues) with PhICl₂ and PhI(OAc)₂ (eq. 2).⁷ While monomeric Pd^IV species have also been proposed as possible intermediates in catalytic C–H functionalization,^1–4 to date such complexes have not been detected from the oxidation of catalytically relevant dimers like 1 and 3.⁵

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We demonstrate herein that the reaction between 3 and various electrophilic trifluoromethylating reagents in the presence of AcOH produces an isolable monomeric Pd^IV product. This Pd^IV complex undergoes C–CF₃ bond-forming reductive elimination, and both the rate and yield of this transformation can be tuned with Lewis/Brønsted acids. Mechanistic investigations of the C–CF₃ bond forming process are described and provide new insights into the potential role of acidic promoters in Pd-catalyzed C–H functionalization.^9,10 Finally, we demonstrate that this Pd^IV species is a catalytically competent intermediate in C–H trifluoromethylation reactions.

Results and Discussion

Synthesis and Characterization of Pd^IV Complex 6

Our initial investigations focused on the reaction of Pd^II dimer 3 with the CF₃⁺ reagents 5a–e¹¹ in AcOH. In all cases, ¹⁹F NMR spectroscopic analysis after 1 h at 40 °C showed the formation of a new Pd–CF₃ product (6) in yields ranging from 2–60% (Table 1, entries 1–5).¹² When the solvent was changed to 1,2-dichloroethane (which has been used as a solvent for Pd-catalyzed C–H trifluoromethylation with similar oxidants),⁹ the reaction of 3 with 5b afforded <2% of 6. However, interestingly, when this same reaction was conducted in the presence of 1–20 equiv AcOH (which is present during catalytic C–H trifluoromethylation, vide infra),⁹ 6 was formed in modest to good yield (Table 1, entries 7–9). Complex 6 was isolated in 60% yield as a pale yellow solid from the reaction of 3 with 3 equiv of 5b in AcOH at room temperature.^12,13

Table 1.

Oxidation of 3 with Different ″CF₃⁺ ″ Reagents

Entry	Solvent	Oxidant	Yield 6
1	AcOH	5a	45%
2	AcOH	5b	60%
3	AcOH	5c	27%
4	AcOH	5d	2%
5	AcOH	5e	4%
6	DCE	5b	<2%
7	DCE/1 equiv AcOH	5b	48%
8	DCE/5 equiv AcOH	5b	56%
9	DCE/20 equiv AcOH	5b	65%

Conditions: Complex 3 (1 equiv) and ″CF₃⁺ ″ reagent (3 equiv) in solvent (0.4 mL) for 1 h at 40 °C. Yields were determined by ¹⁹F NMR spectroscopy and represent an average of at least two independent runs.

¹H and ¹⁹F NMR spectroscopic analysis of complex 6 at room temperature showed that this molecule contains a cyclometalated benzo[h]quinoline, a CF₃ group, and two different acetate ligands. In addition, when samples of 6 were cooled to −40 °C, a broad ¹H NMR resonance integrating to 2 protons was observed at 10.45 ppm, implicating the presence of a coordinated water molecule.

X-ray quality crystals of 6 were obtained by vapor diffusion of pentanes into a concentrated dichloroethane solution. As shown in Figure 1, the crystal structure shows the monomeric Pd^IV complex (bzq)Pd(CF₃)(OAc)₂(OH₂). In the solid state, the aquo ligand is trans to the σ-aryl group, and it participates in two intramolecular hydrogen bonds with the carbonyl oxygens of the acetate ligands.¹⁴ The O_Ac---H bond distances 1.69(5) and 1.82(2) Å are similar to hydrogen bonds reported in IⁱPrPd^II(OAc)₂(OH₂) (1.73 and 1.82 Å, IⁱPr =1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene).¹⁵ The H-bonding interaction in 6 is also apparent by IR spectroscopy (ν_OH(KBr) = 3414 cm⁻¹).

Figure 1.

ORTEP drawing of complex 6. Thermal ellipsoids are drawn at 50% probability, and hydrogen atoms are omitted for clarity expect for those on the H₂O ligand. The structure was solved as two identical structures in a unit cell (only one is shown, see Supporting Information for more information). Selected bond lengths (Å): Pd–C(14) 2.007(4), Pd–C(11) 2.006 (4), Pd–N(1) 2.042(3), Pd–O(1) 2.168(4), Pd–O(2) 2.012(3), Pd–O(4) 2.105(3), Pd–N 2.042(3), O(1)–H(1B) 1.04(2), O(1)–H(1C) 0.84(4), O(3)–H(1B) 1.69(5), O(5)–H(1C) 1.82(2), O(1)–O(3) 2.624(7), O(1)–O(5) 2.547(5). Selected bond angles (°): C(11)–Pd–C(14) 92.72(17), N(1)–Pd–C(14) 91.31(16), O(3)–H(1B)–O(1) 150(7), O(5)–H(1C)–O(1) 143(7).

Complex 6 is remarkable for several reasons. First, this mono-σ-aryl Pd complex is unusually stable at room temperature.² In the solid state, 6 can be stored for at least 1 month without noticeable decomposition; furthermore, the t_1/2 for decomposition in CD₃CO₂D solution is 16 h at 25 °C. Second, 6 is formed under conditions analogous to those reported for catalytic C–H trifluoromethylation (using CF₃⁺ reagents in DCE containing 1–20 equiv of exogenous AcOH),⁹ suggesting the possibility that it is a catalytic intermediate (vide infra). Finally, the formation of 6 shows that dimer 3 can be oxidized to afford monomeric Pd^IV complexes.¹³ This is particularly notable in light of recent work by Ritter, who demonstrated that the reaction of 3 with PhIX₂ (X = Cl, OAc) in dry CH₂Cl₂ at −35 °C produces Pd^III dimers (eq. 2).⁷ On the basis of these studies, he concluded that “bimetallic Pd^III complexes are responsible for a large class of C–H oxidations previously proposed to proceed via Pd^II/IV redox cycles.”^7b In contrast, the current work suggests that factors such as reaction solvent, oxidant structure, ancillary ligands, and temperature are all likely critical in determining the structure(s) of high oxidation state intermediates in such transformations.³

C–CF₃ Bond-Forming Reductive Elimination from 6

Complex 6 could undergo reductive elimination to produce at least three products: bzq–CF₃ (7), bzq–OAc (8a), or bzq–OH (8b) (Table 2). Thus, this system provides an opportunity to assess the relative rates of these different C–CF₃ and C–O bond-forming processes. While C–O bond-forming reductive elimination is well-precedented from palladium(IV)^5b,17 and many other metal centers/oxidation states,¹⁸ C–CF₃ coupling reactions remain extremely rare in organometallic chemistry.^19,20,21

Table 2.

Yield and Product Distribution of Reductive Elimination from 6 as a Function of Solvent

Entry	Solvent	Yield 7	Yield 8a	Yield 8b
1	AcOH	56%	<2%	<2%
2	DCE	54%	<2%	<2%
3	CHCl3	62%	<2%	<2%
4	NO2Ph	57%	<2%	<2%
5	DCE/50 equiv pyridine	<2%	<2%	84%

Conditions: Complex 6 (1 equiv) in solvent (0.26 mL) for 12 h at 60 °C. Yields were determined by ¹⁹F and ¹H NMR spectroscopy and represent an average of at least two independent runs.

Heating 6 at 60 °C for 12 h in a variety of solvents (AcOH, CHCl₃, DCE, and nitrobenzene) produced trifluoromethylated product 7 in 54–62% yield along with <2% of 8a and 8b (Table 2, entries 1–4). We propose that the remarkably high chemoselectivity for C–CF₃ bond formation may be due to hydrogen bonding between the coordinated H₂O and OAc ligands, which slows competing C–O bond coupling. Although no other organic products could be identified in these reactions, we could only account for approximately 60% of the benzo[h]quinoline ligand. The only other recognizable benzo[h]quinoline-containing product was [(bzq)Pd(OAc)]₂ (3), which was formed in <3% yield.²²

Literature reports have described similarly modest mass balance in other oxidatively-induced reductive elimination reactions from Pd.²³ In many of these cases, the addition of pyridine (which can bind to highly reactive, coordinatively unsaturated Pd intermediates) led to improved results.²³ Thus, we also examined the thermolysis of 6 in DCE in the presence of 50 equiv of pyridine. As anticipated, the mass balance improved significantly under these conditions (with 84% of the benzo[h]quinoline ligand accounted for). However, intriguingly, the chemoselectivity of the reaction was reversed, and only the C–O coupled product 8b was detected by ¹H NMR spectroscopic analysis of the crude reaction mixture (Table 2, entry 5). We hypothesize that this dramatic change in selectivity may result from disruption of the H-bonding in 6 (by either deprotonation or displacement of the H₂O ligand by pyridine), which then lowers the barrier for C–O bond formation.

Mechanism of C–CF₃ Bond-Forming Reductive Elimination

The most likely mechanisms for C–CF₃ bond-forming reductive elimination from complex 6 are paths A, B, and C in Figure 2. Path A involves dissociation of an acetate ligand to afford a five-coordinate cationic intermediate (I) followed by C–CF₃ bond-forming reductive elimination to afford 7. Path B proceeds via dissociation of H₂O to generate a neutral 5-coordinate Pd^IV species II and subsequent C–CF₃ coupling. Finally, path C involves direct reductive elimination from octahedral complex 6. Notably, ionic dissociative mechanisms (like path A),^24,25 neutral dissociative mechanisms (like path B),²⁶ and concerted processes (like path C)27 have significant precedent in reductive elimination reactions from octahedral Pd^IV and Pt^IV complexes.

Figure 2.

Three possible mechanisms for C–CF₃ bond-forming reductive elimination from 6

Our first mechanistic studies probed the viability of carboxylate dissociation/exchange (step i of path A). The addition of 20 equiv of AcOH-d₄ or 20 equiv of NMe₄OAc-d₃ to complex 6 in DCE-d₄ led to complete exchange of both acetate ligands within minutes at room temperature (as determined by ¹H NMR spectroscopic analysis) (eq. 3). These results demonstrate that carboxylate ligand substitution is significantly faster than C–CF₃ coupling.

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We next investigated the influence of exogenous NBu₄OAc on C–CF₃ bond-forming reductive elimination from 6. Interestingly, the addition of 1 equiv of NBu₄OAc almost completely shut down the formation of bzq–CF₃ (7); under these conditions, the major identifiable organic products were oxygenated compounds 8a and 8b (Table 3, entry 3). In the presence of smaller amounts of NBu₄OAc (0.2 equiv), 7 was formed, but in significantly lower yield than without this additive (26% versus 54% yield, Table 3, entries 1 and 2, respectively).

Table 3.

Effect of Added NBu₄OAc, NBu₄PF₆, and H₂O on Reductive Elimination from 6

Entry	Additive	Yield 7	Yield 8a	Yield 8b
1	None	54%	<2%	<2%
2	0.2 equiv NBu4OAc	26%	<2%	<2%
3	1 equiv NBu4OAc	2%	16%	16%
4	1 equiv NBu4PF6	56%	<2%	<2%
5	1 equiv H2O	50%	<2%	<2%
6	10 equiv H2O	50%	<2%	<2%

Conditions: Complex 6 (1 equiv) and the appropriate additive in DCE (0.26 mL) for 12 h at 60 °C. Yields were determined by ¹⁹F and ¹H NMR spectroscopy and represent an average of at least two independent runs.

Quantitative kinetic analysis of these transformations was complicated by the presence of an induction period. Nonetheless, it was instructive to compare the reaction profile (yield versus time) in the presence and absence of NBu₄OAc. As shown in Figure 3, the addition of NBu₄OAc significantly increased the induction period and slowed the rate of bzq–CF₃ coupling. In notable contrast, the addition of NBu₄PF₆ had minimal impact on the yield (Table 3, entry 4) or reaction profile (Figure S16) compared to the analogous reaction without additive. This indicates that the dramatic effect of NBu₄OAc is specifically due to the acetate anion.

Figure 3.

Reaction profile for reductive elimination from 6 in DCE at 60 °C in the presence of no additive (black squares), 1 equiv of H₂O (purple triangles), and 0.2 equiv of NBu₄OAc (green diamonds).

Finally, we examined the influence of H₂O on reductive elimination from 6. The addition of 1–10 equiv of H₂O had minimal impact on the overall yield of 7 after 12 h at 60 °C (Table 3, entries 5 and 6). The presence of 1 equiv of H₂O did slow the rate and increase the induction period for this transformation (Figure 3); however, this effect was much smaller than that observed with 0.2 equiv NBu₄OAc.

Summary of Mechanistic Data

On the basis of all of this data, we propose that mechanism A (involving pre-equilibrium acetate dissociation followed by rate-determining C–CF₃ coupling) is a major pathway for C–CF₃ bond formation from 6. The AcOH-d₄ and NMe₄OAc-d₃ exchange experiments indicate that step i of path A is fast relative to C–CF₃ bond-formation. The inhibition of this reaction by exogenous NBu₄OAc (but not by NBu₄PF₆) is consistent with the expected inverse 1^st order dependence on [AcO⁻] (see Figure S10 for derivation of the rate expression). Importantly, the current data do not definitively rule out mechanisms B or C as competing pathways. However, the comparatively small influence of added H₂O on the product distribution, yield, and reaction profile is consistent with mechanism A as the most significant contributor to this transformation.

Effects of Additives on C–CF₃ Bond-Forming Reductive Elimination from 6

On the basis of several literature reports,^5b,18c we hypothesized that pre-equilibrium dissociation of acetate would be promoted by Brønsted acids [e.g., trifluoroacetic acid (TFA)], Lewis acids (e.g., Yb(OTf)₃), and other reagents that react readily with free AcO⁻ [e.g., trifluoroacetic anhydride (TFAA)]. As such, we next examined the effect of these additives on reductive elimination from 6. As shown in Figure 4, the addition of 10 equiv of TFA or TFAA or 1 equiv of Yb(OTf)₃ eliminated the induction period and provided first order kinetic profiles for bzq–CF₃ coupling.

Figure 4.

Reaction profile for reductive elimination from 6 in DCE at 60 °C in the presence of no additive (black squares), 10 equiv of TFA (blue diamonds), 10 equiv of TFAA (green circles), and 1 equiv of Yb(OTf)₃ (red triangles).

Additionally, these additives led to substantial increases in the yield of C–CF₃ coupled product 7 (Table 4). Most notably, with 1 equiv of Yb(OTf)₃, nearly quantitative yield of 7 was obtained (compared to 54% in the absence of this additive).

Table 4.

Effect of Acidic/Electrophilic Additives on Reductive Elimination from 6

Entry	Additive	kobs (s−1)	Yield 7[a]
1	None	nd[b]	54%
2	10 equiv TFA	3.31 ± 0.04 × 10−4	73%
3	10 equiv TFAA	1.43 ± 0.02 × 10−3	84%
4	1 equiv Yb(OTf)3	2.92 ± 0.03 × 10−4	99%

^[a]Conditions: Complex 6 (1 equiv) and the appropriate additive in DCE (0.26 mL) for 12 h at 60 °C. Yields were determined by ¹⁹F and ¹H NMR spectroscopy and represent an average of at least two independent runs.

^[b]k_obs could not be determined for this reaction due to an induction period.

These effects provide further support for mechanism A (Figure 2) as a major pathway for C–CF₃ coupling in this system. Additionally, the observed enhancements in mass balance suggest that the acidic/electrophilic additives may play a role in sequestering reactive, coordinatively unsaturated Pd intermediates formed during the reductive elimination process.

Catalytic Competence of 6 in Pd-Catalyzed C–H Trifluoromethylation

A recent communication by Yu and coworkers demonstrated the Pd(OAc)₂-catalyzed C–H trifluoromethylation of benzo[h]quinoline with oxidants 5b, 5d, and 5e in DCE.⁹ The addition of 1 equiv of Cu(OAc)₂ and 10 equiv of TFA was critical to promote catalytic turnover in these reactions (eq. 4); however, no insights were provided regarding the mechanistic role of these additives. In addition, while the authors speculated that a Pd^II/IV pathway was plausible in this system, no mechanistic experiments were reported.

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We hypothesized that Pd^IV complex 6 might be an intermediate in this catalytic transformation. Using the method of initial rates, we compared the trifluoromethylation of benzo[h]quinoline with 5e using 10 mol % of Pd(OAc)₂ to that with 10 mol % of complex 6 under otherwise identical conditions. As shown in eq. 4, the initial rate with 6 was 18-fold faster than that with Pd(OAc)₂. Furthermore, both catalysts provided similar yields of product 7 when the reactions were followed to completion. These results clearly demonstrate the kinetic competence of 6 and establish the potential viability of this monomeric Pd^IV species as a catalytic intermediate.

Role of Promoters in Catalytic C–H Trifluoromethylation

The demonstration that 6 is a catalytically competent intermediate in C–H trifluoromethylation provided a platform for rationalizing the role that the promoters Cu(OAc)₂ and TFA play in the catalytic cycle. All of the studies described above suggest that these additives are important for both the formation of and C–CF₃ reductive elimination from Pd^IV complex 6. As shown in Table 1, the generation of 6 by oxidation of 3 with CF₃⁺ requires the presence of at least 1 equiv of AcOH. Under the catalytic conditions, the combination of Cu(OAc)₂/TFA would provide an initial source of AcOH through the equilibrium in eq. 5.

$$\mathrm{Cu}{\left(\mathrm{OAc}\right)}_2+\mathrm{TFA}\rightleftharpoons \mathrm{Cu}{\left(\mathrm{TFA}\right)}_2+\mathrm{AcOH}$$ (5)

The results in Table 4 demonstrate that acidic additives can increase the rate, yield, and mass balance of C–CF₃ bond-forming reductive elimination from 6. To test whether catalytically relevant quantities of Cu(OAc)₂/TFA have a similar effect, we studied the thermolysis of 6 in the presence of 10 equiv of Cu(OAc)₂ and 100 equiv of TFA. Under these conditions, reductive elimination occurred extremely rapidly and in nearly quantitative yield (94% compared to 54% in the absence of Cu/TFA) (Figure 5). These results implicate Cu(OAc)₂/TFA in: (i) accelerating reductive elimination from a Pd^IV intermediate like 6 and (ii) limiting competing unproductive decomposition pathways of this high oxidation state complex that reduce the yield of bzq–CF₃ (7).

Figure 5.

Reaction profile of reductive elimination from 6 in the presence of no additive (black squares) and 10 equiv Cu(OAc)₂/100 equiv TFA (orange circles).

Conclusions

In conclusion, this article describes the oxidation of cyclometalated Pd dimer [(bzq)Pd(OAc)]₂ with CF₃⁺ reagents to generate monomeric Pd^IV trifluoromethyl complex 6. This complex undergoes highly chemoselective C–CF₃ bond-forming reductive elimination that is accelerated by acidic additives. Complex 6 is also a kinetically competent catalyst for the Pd-catalyzed trifluoromethylation of benzo[h]quinoline with CF₃⁺ reagents. On the basis of this data, we propose that 6 is a catalytically relevant intermediate in C–H trifluoromethylation reactions. These studies provide new insights into the role of the promoters Cu(OAc)₂ and TFA in the catalytic transformations. Specifically, these additives appear to: (1) serve as a source of AcOH (which is critical for the oxidation of dimeric [(bzq)Pd(OAc)]₂ 3 to monomeric 6) and (2) accelerate and enhance mass balance in C–CF₃ coupling from 6. We anticipate that this (and other related) detailed mechanistic/organometallic investigations of Pd-catalyzed C–H functionalization will facilitate the rational design of new catalysts, promoters, and reagents for these transformations.