Mechanistic and Computational Studies of Oxidatively-Induced Aryl–CF₃ Bond-Formation at Pd: Rational Design of Room Temperature Aryl Trifluoromethylation

Abstract

This article describes the rational design of 1^st generation systems for oxidatively-induced Aryl–CF₃ bond-forming reductive elimination from Pd^II. Treatment of (dtbpy)Pd^II(Aryl)(CF₃) (dtbpy = di-tert-butylbipyridine) with NFTPT (N-fluoro-1,3,5-trimethylpyridium triflate) afforded the isolable Pd^IV intermediate (dtbpy)Pd^IV(Aryl)(CF₃)(F)(OTf). Thermolysis of this complex at 80 °C resulted in Aryl–CF₃ bond-formation. Detailed experimental and computational mechanistic studies have been conducted to gain insights into the key reductive elimination step. Reductive elimination from this Pd^IV species proceeds via pre-equilibrium dissociation of TfO⁻ followed by Aryl–CF₃ coupling. DFT calculations reveal that the transition state for Aryl–CF₃ bond formation involves the CF₃ acting as an electrophile with the Aryl ligand acting as a nucleophilic coupling partner. These mechanistic considerations along with DFT calculations have facilitated the design of a 2^nd generation system utilizing the tmeda (N,N,N’,N’-tetramethylethylenediamine) ligand in place of dtbpy. The tmeda complexes undergo oxidative trifluoromethylation at room temperature.

Introduction

The formation of C–CF₃ bonds is an important transformation for the construction of pharmaceuticals and agrochemicals.¹ Replacing a methyl group with a trifluoromethyl substituent can have a profound effect on the physical and biological properties of a molecule.² As a result, there is high demand for versatile synthetic methods for generating carbon–CF₃ bonds.³ While there has been significant progress in the construction of sp³-carbon–CF₃ linkages,³ there are comparatively fewer methods for Aryl–CF₃ bond-formation.^4,5,6,7

Transition metal-catalyzed cross-coupling between Aryl–X and CF₃–Y would serve as an attractive method for the synthesis of benzotrifluorides.^8,9,10,11 The use of Pd-based catalysts for such transformations is of particular interest because they serve as versatile and widely used catalysts for a variety of other carbon–carbon bond-forming reactions.¹² However, developments in this area have been limited by the challenges associated with a key step of the cross-coupling catalytic cycle, namely Aryl–CF₃ bond-forming reductive elimination from Pd^II centers.^4,13 The vast majority of known Pd^II(Aryl)(CF₃) complexes are inert to Aryl–CF₃ coupling at temperatures as high as 150 °C.^24,21

Two strategies have been utilized in the literature to address this challenge. The first has focused on achieving Aryl–CF₃ bond-forming reductive elimination from Pd^II via steric and electronic modification of the ancillary ligands (L) at (L)_nPd^II(Aryl)(CF₃). For example, pioneering work by Grushin demonstrated that the Xantphos ligand (Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) facilitates high yielding formation of trifluorotoluene from (Xantphos)Pd^II(Ph)(CF₃) at 80 °C (eq. 1).¹⁴ More recently, Buchwald has elegantly demonstrated that the sterically large monodentate phosphine ligand Brettphos (Brettphos = 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl) promotes stoichiometric Aryl–CF₃ coupling from (Brettphos)Pd^II(Aryl)(CF₃) at 80 °C (eq. 2).¹⁵ Remarkably, this latter system was successfully applied to the catalytic trifluoromethylation of aryl chlorides with Et₃SiCF₃ at 130–140 °C.¹⁵

While this first approach has provided important breakthroughs, Pd^II-mediated Aryl–CF₃ bond-forming reactions remain limited by the requirement for specialized and expensive phosphine ligands^16,17 relatively high reaction temperatures (80-140 °C), and the need for expensive Et₃SiCF₃¹⁸ in catalytic processes. As a result, several groups have focused on a second, complementary strategy for achieving Aryl–CF₃ bond-forming reductive elimination from Pd.^19,20,21 This approach hinges on changing the oxidation state, rather than the ancillary ligand environment, at the metal center. As shown in eq. 3, it was expected that palladium(IV) complexes of general structure (L)₂(X)₂Pd^IV(Aryl)(CF₃) (A) would be highly kinetically and thermodynamically reactive towards Aryl–CF₃ coupling. This hypothesis is predicated on literature reports showing that Pd^IV complexes participate in numerous carbon-heteroatom bond-forming reductive elimination reactions that remain challenging at Pd^II centers.^22,23 A key advantage of this approach would be that Pd^IV intermediate A could potentially be accessed using nucleophilic (CF₃⁻)²⁴, electrophilic (CF₃⁺)²⁵, or free-radical (CF₃·)²⁶ based trifluoromethylating reagents.

Two preliminary examples have shown the viability of this approach. First, Yu and coworkers have elegantly demonstrated the Pd^II/IV-catalyzed ligand-directed C–H trifluoromethylation with electrophilic trifluoromethylating reagents (CF₃⁺ reagents).¹⁹ Subsequent stoichiometric studies implicated a mechanism involving: (a) C–H activation to form a cyclometalated Pd^II–Aryl intermediate, (b) oxidation with CF₃⁺ to generate Pd^IV(Aryl)(CF₃), and (c) Aryl–CF₃ bond-forming reductive elimination from Pd^IV to release the product.²⁰

In a second example, our group has shown the viability of stoichiometric Aryl–CF₃ bond-forming reductive elimination from Pd^IV centers bearing σ-aryl ligands that do not contain chelate directing groups.²¹ In this system, the key Pd^IV intermediate is generated via oxidation of a pre-assembled Pd^II(Aryl)(CF₃) species with an N-fluoropyridinium reagent. We report herein a detailed mechanistic study of Aryl–CF₃ bond-forming reductive elimination from Pd^IV in this latter system. This work provides valuable insights into the influence of ancillary ligands, the role of each coupling partner, and the nature of the transition state for this transformation. These mechanistic studies have also allowed us to rationally design the first examples of room temperature Aryl–CF₃ bond-formation from palladium.

Results and Discussion

Development and Scope of Aryl–CF₃ Coupling at Pd^IV.

Our studies began with the synthesis of a series of Pd^II–CF₃ complexes of general structure (dtbpy)Pd^II(Aryl)(CF₃) (1a-i, dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridine). These compounds were prepared by the treatment of (dtbpy)Pd^II(Aryl)(I) with CsF followed by TMSCF₃ in THF at 23 °C (Table 1). The products were isolated as yellow solids in 32-70% yield.²¹ X-ray quality crystals of 1a were obtained by vapor diffusion of pentanes into a dichloromethane solution of 1a, and the X-ray crystal structure of this complex is shown in Figure 1.

Table 1.

Synthesis of Complexes 1a-i

Entry	Aryl	Compound	Isolated Yield
1	p-FC6H4	1a	70%
2	p-CNC6H4	1b	54%
3	p-CF3C6H4	1c	63%
4	p- PhC(O)C6H4	1d	51%
5	p-PhC6H4	1e	58%
6	p-MeOC6H4	1f	32%
7	p-MeC6H4	1g	49%
8	C6H5	1h	47%
9	m-MeC6H4	1i	42%

Figure 1.

ORTEP drawing of complex 1a. Thermal ellipsoids are drawn at 50% probability, hydrogen atoms are omitted for clarity. Selected bond lengths (Å): Pd–C(1) 2.005(3), Pd–C(25) 2.007(4), Pd–N(1) 2.107(2), Pd–N(2) 2.143(3). Selected bond angles (°): C(1)–Pd–C(25) 89.99(13), C(1)–Pd–N(1) 95.58(11), C(1)–Pd–N(2) 169.99(11), C(25)–Pd–N(1) 173.92(12), C(25)–Pd–N(2) 96.67(11).

The Pd^II complexes (1a-i) are inert towards direct Aryl–CF₃ bond-forming reductive elimination. For example, heating 1a at 130 °C for 72 h produced <5% of 4-fluorobenzotrifluoride (2a), and the Pd^II starting material could be recovered in >80% yield (eq. 4). Importantly, similarly low reactivity has been reported in the literature for other (L~L)Pd^II(Aryl)(CF₃) complexes (L~L = diphenylphosphinoethane, diphenylphosphinopropane, and diphenylphosphinobenzene).^24a,b As discussed above, the only demonstrated examples of Aryl–CF₃ bond-forming reductive elimination from Pd^II require relatively high temperatures (80 °C) and specialized phosphine ligands.^14,15a

We reasoned that the 2e⁻ oxidation of (dtbpy)Pd^II(Aryl)(CF₃) would yield a highly reactive Pd^IV adduct that might undergo more facile Aryl–CF₃ bond-forming reductive elimination (eq. 5, i). Thus, we examined the reaction of 1a with N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), and PhI(OAc)₂, which are all well-known to promote the oxidation of Pd^II to Pd^IV.²² As shown in Table 2, all three oxidants reacted rapidly with 1a in nitrobenzene-d₅ at 80 °C. However, the desired trifluoromethylated product was not obtained; instead, the major organic product contained a nucleophile derived from the oxidant (Br, Cl, or OAc, respectively). These results are consistent with the formation of a Pd^IV intermediate, from which Aryl–X (X = OAc, Br, and Cl) bond-forming reductive elimination is significantly faster than Aryl–CF₃ coupling (eq. 5, ii).²¹

Table 2.

Reaction of 1a with Diverse Oxidants (Oxidant–X)

Entry	Oxidant–X	Yield 2a	Yield 3a (X)
1		<5%	75% (Br)
2		<5%	70% (Cl)
3		<5%	20% (OAc)
4		<5%	nd (F)a
5		60%	<5%
6		53%	<5%
7		69%	<5%
8		55%	<5%
9		68%	<5%
10		70%	<5%
11	XeF2	65%	5%

Yields were determined by ¹⁹F NMR spectroscopy and are an average of two runs. nd = not detected.

^a1a accounted for the remaining mass balance.

In an effort to avoid competing reductive elimination processes, we next examined the use of electrophilic fluorinating reagents (F⁺ sources). These reagents were selected based on the hypothesis that fluoride (the X-type ligand introduced to Pd^IV by F⁺ sources) might undergo slower reductive elimination than CF₃ .^22d,27,28 Gratifyingly, a variety of different F⁺ reagents reacted with 1a to afford modest to excellent yields of the trifluoromethylated product 2a after 3 h at 80 °C (Table 2, entries 4-10). The optimal electrophillic fluorinating reagent was N-fluoro-1,3,5-trimethylpyridium triflate (NFTPT), which provided 2a in 70% yield as determined by ¹⁹F NMR spectroscopy.²⁹ Importantly, <5% of products derived from Aryl–F or Aryl–OTf coupling were observed under these conditions.

This transformation was next applied to complexes 1b-i, which contain sterically and electronically diverse aryl groups. As shown in Table 3, the yield of trifluoromethylated product was relatively insensitive to the electronic properties of the arene, and the reaction proceeded with good results in systems containing both electron withdrawing [e.g., CN, C(O)Ph] and electron donating (e.g., CH₃, OCH₃) para- and meta-substituents.³⁰

Table 3.

NFTPT-Promoted Aryl–CF₃ Coupling at Complexes 1a-i

Entry	Compound	Aryl	Yield Aryl–CF3
1	1a	p-FC6H4	70%
2	1b	p-CNC6H4	25%
3	1c	p-CF3C6H4	55%
4	1d	p-PhC(O)C6H4	56%
5	1e	p-PhC6H4	70%
6	1f	p-MeOC6H4	72%
7	1g	p-MeC6H4	66%
8	1h	C6H5	70%
9	1i	m-MeC6H4	64%

Yields were determined by ¹⁹F NMR spectroscopy and are an average of two runs.

At room temperature, the oxidation of 1a by NFTPT produced a single major intermediate. This species (4) was isolated from dichloroethane as a yellow solid in 53% yield (eq 6). Analysis of 4 by ¹⁹F NMR spectroscopy in MeCN-d₃ showed four characteristic resonances: a doublet at −30.9 ppm (Pd–CF₃), a singlet at −79.4 ppm (Pd–OTf), a multiplet at −117.1 ppm (Pd–ArF), and a quartet at −256.5 ppm (Pd–F) in a 3: 3: 1: 1 ratio. In nitrobenzene-d₅, broad resonances were observed with similar chemical shifts in the same 3: 3: 1: 1 ratio.³¹ The ¹H NMR spectrum of 4 showed two singlets at 8.47 and 8.40 ppm (5,5′ protons of dtbpy) as well as two singlets at 1.49 and 1.41 ppm (^tBu groups of dtbpy).

X-ray quality crystals were obtained via vapor diffusion of pentanes into a DCE solution of 4. As shown in Figure 2, the solid state structure of 4 shows the octahedral Pd^IV species (dtbpy)Pd(p-FC₆H₄)(CF₃)(F)(OTf). Interestingly, the Pd–CF₃ bond distance in 4 (2.009(4) Å) is nearly identical to that of the Pd^II–CF₃ starting material 1a (2.005(3) Å). However, the Pd–N bond lengths of 4 (2.038(4) and 2.082(4) Å) are significantly shorter than those in 1a (2.107(2) and 2.143(3) Å).

Figure 2.

ORTEP drawing of complex 4. Thermal ellipsoids are drawn at 50% probability, hydrogen atoms are omitted for clarity. Selected bond lengths (Å): Pd–C(1) 2.009(5), Pd–C(25) 2.018(5), Pd– N(1) 2.038(4), Pd–N(15) 2.082(4), Pd–O(1) 2.226(3). Selected bond angles (°): C(19)–Pd–C(25) 91.09(15), C(19)–Pd–N(15) 92.18(16), C(25)–Pd–N(15) 175.68(17), C(19)–Pd–F(1) 91.09(15), C(25)–Pd–F(1) 83.31(16), C(19)–Pd(1)–O(1) 175.74 (16), C(25)–Pd(1)–O(1) 95.15 (16).

Mechanistic Study of Aryl–CF₃ Bond-Forming Reductive Elimination from Pd^IV.

There are at least three possible pathways for Aryl–CF₃ bond-forming reductive elimination from 4, mechanisms A, B, and C (Figure 3). Mechanism A involves initial triflate dissociation to form a cationic five-coordinate Pd^IV intermediate I and subsequent Aryl–CF₃ bond formation. Mechanism B involves fluoride dissociation, followed by Aryl–CF₃ coupling from intermediate II. Mechanism C proceeds via concerted C–CF₃ bond-forming reductive elimination. Notably, there is significant literature precedent for both ionic^{22e,Error! Bookmark not defined.,32,33} and concerted^22e,34 reductive elimination mechanisms from octahedral group 10 metal complexes.

Figure 3.

Three potential mechanisms for Aryl–CF₃ bond formation from 4.

Order in triflate.

The addition of 1 equiv of NBu₄OTf to the thermolysis of 4 in NO₂Ph-d₅ at 50 °C significantly slowed the initial rate of formation of 2a (from 2.21 × 10⁻⁵ M s⁻¹ to 1.35 × 10⁻⁵ M s⁻¹).³⁵ Furthermore, an excellent linear fit was observed for a plot of initial rate versus 1/[NBu₄OTf] (Figure 4).

Figure 4.

Plot of initial rate versus 1/[OTf] for reductive elimination from 4 to form 2a in PhNO₂-d₅ at 50 °C. y = 1.91 × 10⁻⁷ + 9.86 × 10⁻⁶; R² = 0.998.

In order to confirm that the presence of TfO⁻ was responsible for the observed effect, this reaction was next examined in the presence of NBu₄PF₆, which contains a non-coodinating anion. The use of 1 equiv of NBu₄PF₆ under otherwise identical conditions resulted in a >2-fold increase in the initial rate of reductive elimination to 5.57 × 10⁻⁵ M s⁻¹. This result indicates that inibition by NBu₄OTf is specifically due to the TfO⁻ anion. Furthermore, it suggests that enhancing the polarity of the medium (by adding non-coordinating ions) accelerates Aryl–CF₃ reductive elimination. Both pieces of data are consistent with ionic mechanism A operating in this system, as reflected by the rate expression in eq. 7.³⁶

Activation parameters.

The initial rate of C–CF₃ bond-forming reductive elimination from 4 in NO₂Ph-d₅ was next examined as a function of temperature. An Eyring plot of the data showed that ΔH^‡ is +29.1 ± 0.2 kcal/mol, while ΔS^‡ = +9.48 ± 0.8 eu. The observed entropy of activation indicates a significant increase in disorder in the transition state for this reductive elimination reaction. Similar values have been observed for carbon-heteroatom bond-forming reductive elimination reactions from Pd^IV that proceed by ionic mechanisms.^22e,23e,37 For example, C–OAc reductive elimination from Pd^IV complex (phpy)₂Pd^IV(OAc)₂ (phpy = 2-phenylpyridine), which is proposed to involve pre-equilibrium dissociation of an acetate ligand, showed ΔS^‡ of +4.2 ± 1.2 eu.^22e

Electronic effects.

Finally, electronic effects on reductive elimination were evaluated using Pd^IV complexes containing p-fluoro, p-methyl, and p-trifluoromethyl-substituted aryl groups (complexes 4-6). Thermolysis of 4, 5, and 6 at 80 °C in NO₂Ph-d₅ for 3 h afforded the corresponding benzotrifluorides in 77%, 93%, and 65% yield, respectively (Table 4). The initial rates of reductive elimination from these complexes at 50 °C in NO₂Ph-d₅ show that electron donating substituents accelerate the reaction. For example, with X = CH₃ (5), the initial rate is more than 20 times greater than with X = F (4). Additionally, when X = CF₃ (6), the initial rate is nearly two times slower than from 4 (Table 4).

Table 4.

Initial Rates of Aryl–CF₃ Bond-Forming Reductive Elimination from Complexes 4-6

Entry	X	Yield Aryl–CF3	Initial rate (M s−1) × 105
1	CH3	93%	45.8
2	F	77%	2.21
3	CF3	65% a	1.43

Reactions were run in duplicate and yields were determined by ¹⁹F NMR spectroscopy.

^a1,4(bistrifluoromethyl)biphenyl formed in 21% yield.

While Table 4 clearly shows that electron-donating aryl substituents accelerate this reaction, it is challenging to definitively interpret this data in the context of the C–CF₃ bond-forming event. Mechanism A is a two-step process involving triflate dissociation followed by Aryl–CF₃ coupling. Thus, the faster rate with complex 5 may be due to the stronger trans effect of a more electron donating σ-aryl ligand and/or from a partial positive charge buildup on the aromatic ring in the transition state for Aryl–CF₃ coupling.

DFT calculations.

We next turned to DFT calculations to more fully explore the mechanism of Aryl–CF₃ bond formation. The complex [(bpy)Pd^IV(Ph)(CF₃)(F)(OTf)] (7) (bpy = 2,2′-bipyridyl, eq. 8) was employed as a model for 5 (Table 4), and the CEP-31G(d)^38,39 basis set and M06^40,41 functional were used along with a single point solvent correction in nitrobenzene (SMD solvation model).⁴² As shown in eq. 8, the calculated ΔH₂₉₈ for loss of TfO⁻ from 7 in nitrobenzene to form cationic intermediate ([(bpy)Pd^IV(Ph)(CF₃)(F)]⁺ (8)) is 15.0 kcal/mol. Furthermore, the activation enthalpy (ΔH^‡₂₉₈) for Ph–CF₃ bond-forming reductive elimination from 8 is 13.7 kcal/mol. Thus, we calculate that mechanism A has an overall ΔH^‡₂₉₈ of 28.7 kcal/mol, which is in excellent agreement with the experimental value (+29.1 ± 0.2 kcal/mol, vide supra).

As discussed above, we observe experimentally that trifluoromethylated products are formed selectively over the corresponding fluorinated compounds. To gain further insights into this selectivity, we used DFT to examine the transition state for Ph–F bond-forming reductive elimination from intermediate 8. As shown in eq. 8, ΔH^‡_{298 (DFT)} from Ph–F coupling is 14.7 kcal/mol. As such, this is a higher energy pathway than Ph–CF₃ bond-formation (ΔΔH^‡_{298 (DFT)} = 1 kcal/mol), consistent with the experimental results.

The calculated charge distribution of intermediate 8 using Natural Bond Order (NBO) analysis^43,44 indicates that the CF₃ carbon carries a significant positive charge (+1.18), while the α-carbon of the phenyl ligand bears a charge of +0.07.⁴⁵ This charge difference is amplified in the transition state for C–CF₃ bond-forming reductive elimination, where the CF₃ carbon carries an enhanced positive charge of +1.24, and the charge on the Ph carbon decreases to −0.11. These data imply that the Ph group is acting as the nucleophile during the bond-forming event. This is in sharp contrast to other reports of reductive elimination from Pd^IV in which the aryl or alkyl ligand typically serves as the electrophilic coupling partner.^22,23

We next used DFT to determine the transition state enthalpies (ΔH^‡₂₉₈) for Aryl–CF₃ coupling from complexes of general structure [(bpy)Pd^IV(p-XC₆H₄)(CF₃)(F)]⁺. As expected based on the NBO analysis, ΔH^‡₂₉₈ was smallest with electron donating para substituents (X) on the aromatic ring, consistent with a transition state involving nucleophilic attack by σ-aryl ligand on the CF₃ moiety (Table 5). Furthermore, the ΔH^‡₂₉₈ values showed better correlation with Hammett σ⁺ values for X than the corresponding σ or σ⁻ parameters. This implicates significant resonance effects in the transition state for Aryl–CF₃ coupling.⁴⁶

Table 5.

Gas Phase Values of ΔH^‡₂₉₈ for C–CF₃ Bond-Formation from [(bpy)Pd^IV(p-XC₆H₄)(CF₃)(F)]^+[a]

X	ΔH‡298 (kcal/mol)	σ +
NMe2	6.89	−1.70
NH2	7.10	−1.30
OH	7.71	−0.92
OMe	7.86	−0.78
SMe	7.79	−0.60
Me	9.19	−0.30
F	8.41	−0.07
H	9.41	0
CF3	9.43	0.53
CN	9.23	0.71
NO2	9.23	0.78

^[a]Complexes are calculated using CEP-31G(d)/M06 level of theory.

Finally, we sought to identify supporting ligands that would lower the energy barrier for Ph–CF₃ bond-forming reductive elimination in this system. Literature studies have shown that (tmeda)Pd^IV(CH₃)₂(Ph)(I) (tmeda = tetramethylethylenediamine) is significantly more reactive towards C–C bond-forming reductive elimination than its bipyridine analogue (bpy)Pd^IV(CH₃)₂(Ph)(I)⁴⁷. Thus, we hypothesized that using tmeda in place of dtbpy in our system might impart a similar effect. Consistent with this hypothesis, DFT calculations show that the nitrobenzene solvent-corrected transition state enthalpy (ΔH^‡₂₉₈) for formation of trifluorotoluene from [(tmeda)Pd^IV(Ph)(CF₃)(F)]⁺ is 0.8 kcal/mol lower than that for the analogous bpy complex (12.9 versus 13.7 kcal/mol) (eq. 9). Furthermore, ΔH₂₉₈ for the loss of OTf⁻ from [(tmeda)Pd^IV(Ph)(CF₃)(F)(OTf)] is >10 kcal/mol lower than that from 7 (4.2 versus 15 kcal/mol). Thus, the calculated overall ΔH^‡₂₉₈ for reductive elimination from the tmeda complex is 17.1 kcal/mol, suggesting that Aryl-CF₃ coupling should proceed at significantly lower temperatures than from 7.

Room Temperature Arene Trifluoromethylation.

To assess the effect of diamine ligands experimentally, a series of (N~N)Pd^II(Ph)(CF₃) complexes (9, 10, and 11e) were prepared by the reaction of (N~N)Pd^II(Ph)(I) with CsF followed by TMSCF₃ (see Supporting Information for full details).⁴⁸ Treatment of 9, 10, and 11e with NFTPT under our standard conditions (80 °C for 3 h in NO₂Ph) resulted in clean formation of trifluorotoluene in modest to excellent yield (Table 6). The readily available and inexpensive tmeda ligand was particularly effective. Tmeda complex 11e afforded 90% yield of trifluorotoluene at 80 °C (entry 4), and, most remarkably, provided 83% yield at room temperature (entry 5). To our knowledge, this is first example of room temperature arene trifluoromethylation at a Pd center.⁴⁹

Table 6.

NFTPT-Promoted Aryl–CF₃ Coupling from Complexes 1f, 9, 10, and 11e

Entry	Compound	N~N	Temp	Yield Ph–CF3
1	1f	dtbpy	80 °C	66%
2	9		80 °C	99%
3	10		80 °C	40%
4	11e		80 °C	90%
5	11e		23 °C	83%

Reactions were run in duplicate and yields determined by ¹⁹F NMR spectroscopy.

The scope of room temperature oxidative trifluoromethylation from (tmeda)Pd^II(Aryl)(CF₃) was found to be quite broad.⁵⁰ These reactions proceeded efficiently and in high yield with electron donating and electron neutral substituents on the σ-aryl ligand (for example, Table 7, entries 4-7). The room temperature reactions were lower yielding with arenes bearing highly electron-withdrawing substituents like CF₃ and CN (entries 2 and 3), which is consistent with the proposed transition state (vide supra). Finally, tmeda complexes containing ortho-substituted aryl groups underwent high yielding room temperature oxidative trifluoromethylation (entries 8 and 9). In contrast, these were poorly effective substrates in the dtbpy system, even at 80 °C.³⁰

Table 7.

Synthesis and Reactivity of (tmeda)Pd(Aryl)(CF₃) Complexes

Entry	Compound	Aryl	Yield Aryl–CF3 (80 °C)	Yield Aryl–CF3 (23 °C)
1	11a	p-FC6H4	81%	78%
2	11b	p-CF3C6H4	76%a	52%a
3	11c	p-CNC6H4	60%	22%
4	11d	p-MeOC6H4	92%	95%
5	11e	C6H5	94%	88%
6	11f	p-MeC6H4	90%	83%
7	11g	m-MeC6H4	95%	95%
8	11h	o-MeC6H4	85%	88%
9	11i	o-MeOC6H4	90%	99%

These reactions were conducted at 80 °C for 3 h and at 23 °C for 1 h. Reactions were run in duplicate and all of the starting material was consumed. Yields were determined by ¹⁹F NMR spectroscopy.

^aAt both temperatures, trifluorotoluene was formed in 13% yield.

Conclusion.

This article describes the rational design of 1^st generation systems for oxidatively-induced Aryl–CF₃ bond forming reductive elimination from Pd. Experimental mechanistic studies implicate Aryl–CF₃ coupling from a cationic five-coordinate intermediate, and DFT suggests that the CF₃ ligand serves as the electrophilic partner during bond formation. Our investigations into the scope and mechanism of this reaction have facilitated the development of a 2^nd generation ligand system that enables Aryl–CF₃ coupling at room temperature. This work provides the basis for the design of novel Pd^II/IV-catalyzed trifluoromethylation reactions of aryl metal species (metal = B, Sn, Si) or simple arene C–H bonds. Efforts in this area are currently underway in our group and will be reported in due course.