Opening a Pandora’s Flask on a Prototype Catalytic Direct Arylation Reaction of Pentafluorobenzene: The Ag2CO3/Pd(OAc)2/PPh3 System

Direct C–H functionalization reactions have opened new avenues in catalysis, removing the need for prefunctionalization of at least one of the substrates. Although C–H functionalization catalyzed by palladium complexes in the presence of a base is generally considered to proceed by the CMD/AMLA-6 mechanism, recent research has shown that silver(I) salts, frequently used as bases, can function as C–H bond activators instead of (or in addition to) palladium(II). In this study, we examine the coupling of pentafluorobenzene 1 to 4-iodotoluene 2a (and its analogues) to form 4-(pentafluorophenyl)toluene 3a catalyzed by palladium(II) acetate with the commonplace PPh3 ligand, silver carbonate as base, and DMF as solvent. By studying the reaction of 1 with Ag2CO3/PPh3 and with isolated silver (triphenylphosphine) carbonate complexes, we show the formation of C–H activation products containing the Ag(C6F5)(PPh3)n unit. However, analysis is complicated by the lability of the Ag–PPh3 bond and the presence of multiple species in the solution. The speciation of palladium(II) is investigated by high-resolution-MAS NMR (chosen for its suitability for suspensions) with a substoichiometric catalyst, demonstrating the formation of an equilibrium mixture of Pd(Ar)(κ1-OAc)(PPh3)2 and [Pd(Ar)(μ-OAc)(PPh3)]2 as resting states (Ar = Ph, 4-tolyl). These two complexes react stoichiometrically with 1 to form coupling products. The catalytic reaction kinetics is investigated by in situ IR spectroscopy revealing a two-term rate law and dependence on [Pdtot/nPPh3]0.5 consistent with the dissociation of an off-cycle palladium dimer. The first term is independent of [1], whereas the second term is first order in [1]. The observed rates are very similar with Pd(PPh3)4, Pd(Ph)(κ1-OAc)(PPh3)2, and [Pd(Ph)(μ-OAc)(PPh3)]2 catalysts. The kinetic isotope effect varied significantly according to conditions. The multiple speciation of both AgI and PdII acts as a warning against specifying the catalytic cycles in detail. Moreover, the rapid dynamic interconversion of AgI species creates a level of complexity that has not been appreciated previously.


■ INTRODUCTION
Metal-mediated direct C−H bond functionalization reactions have been studied extensively as cost-effective, eco-friendly, and sustainable synthetic chemistry alternatives to conventional cross-coupling reactions, with enhanced atom economy (at least in substrate) and less metal waste. 1 The strategies are most commonly applied to aryl−aryl bond formation as it avoids the prefunctionalization of aromatics/heteroaromatics with electropositive heteroatoms. 2,3A wide range of aromatic hydrocarbons have been shown to undergo C−H bond functionalization reactions in the presence of carboxylates, 4 and this method has been successfully applied to the functionalization of electron-rich (e.g., indole), 5,6 neutral (e.g., benzene), 7 and poor (e.g., pyridine N-oxide) 8 aromatic systems.The direct arylation of a fluoroarene 9−19 is an example with significant industrial interest for the potential in accessing fluorinated compounds without presynthesized organometallic species. 20,21−27 In this paper, we address a prototype example: the cross-coupling of aryl iodides with pentafluorobenzene catalyzed by palladium acetate with silver carbonate as the added base.
The catalytic cycle for the direct arylation of polyfluoroarenes has been proposed to involve ambiphilic metal ligand activation (AMLA) or concerted metalation deprotonation (CMD) 28−31 between an aryl-Pd κ 1 -carboxylate intermediate and the fluoroaromatic reactant (Scheme 1a). 30The AMLA (6)  transition state is characterized by the agostic interaction of the arene substrate at the same time as the interaction of the arene hydrogen with the carbonyl of the coordinated carboxylate.This mechanism highlights the potential to enhance the reactivity of typically inert bonds by a combination of multiple weak interactions working in synergy; the H-bonding interaction between the C−H bond and the carboxylate ligand increases the electron density on the C−H bond, and the resulting enhancement in the agostic interaction polarizes the C−H bond and increases the acidity of the proton. 30The reactivity of isolated metal complexes in stoichiometric reactions has been used as the evidence for proposing catalytic intermediates in the AMLA (6) mechanism.This approach was highlighted by Wakioka and co-workers who reported the stoichiometric reaction of a preformed dinuclear [Pd(Ar)(μ-OAc)(PPh 3 )] 2 (Ar = Ph, 2-MeC 6 H 4 , 2,6-Me 2 C 6 H 3 ) complex with 3-methylthiophene 32 and benzothiazole. 33A mononuclear complex, Pd(Ar)(κ 2 -OAc)(PPh 3 ), was proposed as the active catalytic species based on the equilibrium with the dinuclear [Pd(Ar)(μ-OAc)(PPh 3 )] 2 in solution and the isolation of stable mononuclear [Pd(Ar)(N-BT)(κ 1 -OAc)(PPh 3 )] (BT = benzothiazole).
In Scheme 1a, the base is written as Y 2 CO 3 with no particular role for the cation, Y, other than to remove YX, as highlighted for AgI. 10 In the frequent situation that the base is silver carbonate or another silver salt, this mechanistic hypothesis has been unraveling.−44 Evidence comes from the detection of silver aryl complexes, H/D exchange reactions, and study of the kinetics of cross-coupling; a scheme summarizing the evidence may be found in ref 45.−49 We recently reported 45 that the reaction of Ag 2 CO 3 with XPhos in the presence of pentafluorobenzene yields Ag(C 6 F 5 )(XPhos) and showed that this is a mononuclear complex that is linear at silver.Its 31 P{ 1 H} NMR spectra show characteristic large couplings to 107 Ag and 109 Ag (51.8 and 48.2% abundance, respectively).It undergoes ready exchange with free XPhos or its tBu analogue by an associative mechanism on a timescale of a few seconds.This complex reacts stoichiometrically with PdI(C 6 H 5 )(XPhos) to form the cross-coupling product C 6 H 5 -C 6 F 5 .Catalytic cross-coupling can be achieved with 5 mol % Ag(C 6 F 5 )(XPhos) as the sole silver source. 45These results led us to propose a catalytic cycle (Scheme 1b) in which the C−H activation step occurs at silver and is followed by transmetalation to palladium prior to C−C bond formation.This cycle may compete with a cycle in which C−H activation occurs at palladium as in Scheme 1a.Although heterobimetallic Ag−Pd species are also plausible intermediates, no experimental evidence has been found to support their involvement. 50,51heme 1.

Organometallics
Palladium catalyst speciation, particularly involving Pd(0)L n species, is affected by the type of phosphine, solvent, additives, and reaction conditions in general.For Xphos and PPh 3 , there is experimental evidence that Pd(0)L n species can form from mixtures of Pd(OAc) 2 /phosphine ligand. 52−55 For the purposes of this paper, we refer to the active catalyst species being Pd(0)L n , which is supported by our global findings (see later).
The study of phosphines coordinated to silver is greatly aided by the presence of two I = 1 / 2 isotopes of silver (see above).Muetterties and Alegranti showed that Ag(Pp-tol 3 ) n species are extremely labile (activation energy for Ag−P rupture in [Ag(Pp-tol 3 ) 4 ]NO 3 is 9 ± 1 kcal/mol).The lability prevents observation of coupling at room temperature, but the coupling constants can be measured from low-temperature spectra, revealing a trend according to the number of phosphine ligands: 57 [Ag(Pp-tol 3 ) n ]PF 6 J( 107 Ag−P) n = 4, 224 Hz; n = 3, 321 Hz; n = 2, 496 Hz.−61 At a more detailed level, the value of J(Ag−P) is associated with the scharacter of the hybrid orbitals of Ag and P via the Fermi contact term.−63 In keeping with Muetterties and Alegranti's early work, later authors have found that PPh 3 is very labile at silver, so measurements of J(Ag−P) typically require low temperatures.
In our previous paper, 45 we showed that silver carbonate reacts with pentafluorobenzene and PPh 3 leading to a new ortho-fluorine resonance in the 19 F NMR and a broad singlet in the 31 P{ 1 H} NMR spectrum with no apparent coupling to 107 Ag or 109 Ag at room temperature.However, the 31 P{ 1 H} signal splits into several resonances with conspicuous coupling to Ag nuclei on cooling to −100 °C, indicating the presence of multiple species at equilibrium (Table S8).At the same time, several 19 F resonances were observed at low temperature around δ −100, characteristic of the ortho-F of Ag(C 6 F 5 ) species.The complex speciation contrasted with the corresponding reaction with XPhos that led to a single species, Ag(C 6 F 5 )(XPhos).Our earlier work as well as the related studies relied on the use of more specialist phosphines, leaving it unclear to what extent the results could be generalized.In this paper, we return to the use of the everyday phosphine, PPh 3 , and investigate the effect of different parameters on the palladium-catalyzed cross-coupling reaction of 4-iodotoluene with pentafluorobenzene leading to improved understanding of the optimum reaction conditions.We also investigate the reaction of the carbonate and bicarbonate complexes of Scheme 2 with pentafluorobenzene in the absence of palladium and show that they are capable of C−H bond activation, albeit with complex speciation.
Instead of following the reaction by conventional solution NMR spectroscopy that is hampered by the suspensions formed with insoluble salts, we adopted two different techniques: high-resolution magic angle spinning (HR-MAS) NMR spectroscopy and in situ IR spectroscopy.−71 We observed several Pd intermediates involved in the catalytic direct arylation reaction of pentafluorobenzene by HR-MAS NMR spectroscopy and confirmed their identity by ex situ MS analysis.These species were also studied in stoichiometric reactions to discriminate between the key catalytic intermediates.In situ IR spectroscopy allows the catalytic reaction to be monitored in a stirred, temperature-controlled flask attached to a Schlenk line, revealing that the kinetics requires a two-term rate law and that the kinetic isotope effect varies with conditions.Our study shows that (a) the reaction with PPh 3 is complicated by multiple speciation with both silver and palladium coordination; (b) Ag(I) plays a direct role in C−H bond activation; and (c) there are two very different pathways for catalytic reaction, resulting in unusual kinetic behavior.

Effect of Reaction Conditions on Catalytic Conversion to Biaryls.
The direct arylation of 4-iodotoluene 2a with pentafluorobenzene 1 was selected as the model reaction system (Reactions R1). 72Quantitative conversion of substrate 2a was observed, and the product 4-(pentafluorophenyl)-Scheme 2. Carbonate and Bicarbonate Complexes of Silver with Phosphine Ligands Organometallics toluene 3a was isolated in 84% yield after purification.Conversion of 2a after 24 h was determined from the integration of the methyl 1 H signals of reagent 2a and product 3a at δ 2.31 and 2.44, respectively.The homocoupling sideproduct 4,4′-dimethyl-1,1′-biphenyl was formed in trace quantities for the reaction of 2a with over 10 mol % of Pd catalyst loading or the reaction in the absence of the Ag I additive but was otherwise absent.The methyl protons of this biaryl side-product were observed at δ 2.40 and did not interfere with the analysis.
The role of the acetate ligands on the precatalyst Pd(OAc) 2 (we abbreviate high-purity nitrite-free Pd 3 (OAc) 6 to Pd(OAc) 2 throughout the paper) was studied by comparing the yields of biaryl product 3a for reactions using Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , and PdCl 2 precatalysts, in each case with 0.75 equiv Ag 2 CO 3 (Table 1).Results comparable with Pd(OAc) 2 + 10 mol % PPh 3 (100% NMR yield, 84% isolated yield) were obtained for reactions catalyzed by Pd(PPh 3 ) 4 and Pd(PPh 3 ) 2 Cl 2 .The ligand PPh 3 , particularly in excess greater than 3, is understood to play a role in both the reduction of Pd II to Pd 0 and the stabilization of the oxidative addition complex in stoichiometric studies. 73e also investigated the effect of changing the base on the catalytic reaction (Table S1).Of the metal carboxylates tested, Ag 2 CO 3 resulted in the highest conversion of substrate 2a and yield of the isolated product 3a.Similar yields were obtained with Pd(OAc) 2 + 10 mol % PPh 3 + 1. Alternative solvents utilized in the literature for C−H bond functionalization reactions include dialkyl carbonates, PEG, and water. 75The polar aprotic solvents such as dimethylacetamide (DMAc) and N-methyl 2-pyrrolidone (NMP) resulted in comparable yields to DMF (Table S2).Ethylene carbonate and propylene carbonate afforded 3a in reasonable yields.
Under the standard conditions, the reaction solution remains clear until the reaction is ca.70% complete, but subsequently, the solution darkens, suggesting the formation of Pd metal (or possibly Ag).The use of preformed stabilized Pd nanoparticles (Pd-NPs) as an alternative to Pd(OAc) 2 precatalyst was therefore examined to establish the type of catalyst (homogeneous and/or heterogeneous) involved in the reaction, recognizing that stabilized PdNPs are usually less active than naked, polar aprotic solvent stabilized PdNPs. 76,77he catalytic activities of Pd-NPs supported on polyvinylpyrrolidone (PVP) of different polymer weights and particle sizes were tested (Table S4) while maintaining the molar quantity of the Pd at 5 mol %.The reaction at 70 °C required PPh 3 , and the isolated yields were significantly lower than when using Pd(OAc) 2 precatalyst.
The structure−reactivity relationship between the electronic properties of the fluoroarenes and the reaction rates was studied to characterize the transition state based on a modified Hammett equation.The electronic properties of fluoroarenes were tuned by varying the substituents on the C1 position of 2,3,5,6-tetrafluorobenzene. 78Functional groups with electronic properties ranging from electron-donating dimethylamino to electron-withdrawing trifluoromethyl were selected.The reactions of these fluoroarenes achieved quantitative conversion of the starting material to the desired products after 20 h at 70 °C.The substituent effect was determined from relative yields obtained by competition reaction between 4-iodotoluene with 10 equiv each of the 1-X-2,3,5,6-tetrafluorobenzene (X = NMe 2 , OMe, F, Cl, and CF 3 ) and pentafluorobenzene analyzed by 19 F NMR (eq 2).
The Hammett equation was modified by substitution of the relative reaction rates represented by the ratio of the two product concentrations (P X /P F ) with the standard set as X = F instead of X = H (eq 1). 79Modest increases in yields were achieved with more electron-withdrawing functional group in the C1 position (Table S5).A linear free-energy relationship (LFER) was observed with the logarithms of the relative yields directly proportional to σ + (Figure 1) yielding R 2 of 0.954.The reaction constant (ρ) determined from the slope of the LFER was +0.28 ± 0.02, consistent with the AMLA(6) pathway that is expected to favor electron-withdrawing substituents stabilizing the negative charge at the TS.(PPh 3 ) 2 (κ 2 -OAc) (see below) in place of Ag 2 CO 3 + PPh 3 yielded 37% deuteration.
When AgOAc (1 equiv) and PPh 3 (2 equiv) were reacted with pentafluorobenzene (10 equiv), no Ag(C 6 F 5 )-containing product was detected by 19 F{ 1 H} NMR spectroscopy.Replacement of AgOAc by Ag 2 CO 3 (1 equiv) resulted in the detection of an Ag(C 6 F 5 )-containing product with ortho-F resonances centered at δ −106.5 (in CH 3 CN).The reaction of AgOAc (1 equiv) or Ag 2 CO 3 (1 equiv) with C 6 F 5 H (10 equiv) in the absence of phosphine did not generate any detectable Ag(C 6 F 5 ) complex, indicating that the PPh 3 ligand is critical for C−H activation (Table S6).To investigate this reactivity further, the PPh 3 -coordinated Ag carbonate complexes in Scheme 2 were synthesized following literature methodologies, 56 together with Ag(PPh 3 ) 2 (κ 2 -OAc). 81he Ag−PPh 3 bond was found to be highly labile at room temperature, resulting in a singlet at room temperature in the 31 P{ 1 H} NMR spectrum of these complexes.The complexes {Ag(PPh 3 ) 2 (κ 2 -HCO 3 )} 2 and {Ag(PPh 3 ) 2 } 2 (μ-κ, 2 κ 1 -CO 3 ) were characterized using low-temperature 31 P{ 1 H} NMR spectroscopy.The {Ag(PPh 3 ) 2 (κ 2 -HCO 3 )} 2 complex existed as a well-defined species in solution, and the 31 P{ 1 H} NMR spectrum was fully resolved at −80 °C to reveal a pair of overlapping doublets centered at δ 9.78 with coupling constants 1 J 31 P − 107 Ag = 465 Hz and 1 J 31 P − 109 Ag = 537 Hz (Figure 2a).These values may be compared with those for [Ag-(XPhos)] 2 (CO 3 ) of 634 and 731 Hz; the reduction in the PPh 3 complex relative to the XPhos complex reflects the increased coordination number of Ag. 57−60 In contrast, the low-temperature 31 P{ 1 H} NMR showed that {Ag(PPh 3 ) 2 } 2 (μκ, 2 κ 1 -CO 3 ) exists in equilibrium with multiple Ag−PPh 3 containing species.Most of the resonances appeared as overlapping doublets with characteristic Ag−P coupling; the chemical shifts and coupling constants of the major species could be identified clearly, but other peaks were difficult to distinguish due to peak overlap (Figure 2b, Table S9).The distinguishable coupling constants varied from 317 to 778 Hz for 109 Ag, indicating the presence of species with a wide range of coordination numbers.Thus, the published crystal structure 56 represents one of many different species that are formed in solution.Because carbonate can act as a bridging ligand in several different ways, 82 we can envisage numerous different oligomeric structures.
The phosphine-coordinated Ag complexes were reacted with C 6 F 5 H (10 equiv) to examine the C−H activation capabilities of these complexes.The presence of a C−H activation product, Ag(C 6 F 5 )(PPh 3 ) n , was detected by the ortho-F resonance at δ −106 using 19 F{ 1 H} NMR spectroscopy with [Ag(PPh 3 ) 2 ] 2 CO 3 •2H 2 O.Because the structure of the resulting Ag(C 6 F 5 )(PPh 3 ) n complex is poorly defined, percent conversions could not be measured accurately.Only when Cs 2 CO 3 is added is a reaction between {Ag(PPh 3 ) 2 (κ 2 -HCO 3 )} 2 and C 6 F 5 H observed, either at 60 °C or at room temperature (Table 2).We also tested Ag(PPh 3 ) 2 (κ 2 -OAc) for reaction with C 6 F 5 H but found no evidence for C−H activation.These experiments show that the carbonate complex [Ag- activation but not the bicarbonate complex or the acetate complex.
To study Ag(C 6 F 5 )(PPh 3 ) n further, an authentic sample of Ag(C 6 F 5 ) was prepared by literature methods 83 and then reacted with PPh 3 (2 equiv) in acetonitrile (Reaction R4).The resulting product was isolated from solution as brown crystals and characterized by low-temperature NMR spectroscopy (Figure 2c).The 31 P{ 1 H} NMR spectrum showed five major pairs of Ag-coupled doublets and one minor pair (Table S10).Considering the tetrameric structure of several silver aryl complexes 84−86 and the infinite chain structure of Ag(C 6 F 5 )-(EtCN) 2 , 83 the presence of multiple species at low temperature may indicate both variable numbers of coordinated phosphines and formation of different oligomers.
It seemed likely that the amount of silver salt could be reduced to catalytic quantities if an alternative stoichiometric base was employed.The catalytic abilities of silver carbonate and the Ag-carbonate triphenylphosphine complexes were tested employing Cs 2 CO 3 (0.75 equiv) as the base in each reaction (Table 3).When Cs 2 CO 3 is used alone for the standard catalytic direct arylation reaction, the conversion after heating for 23 h is 69%.Trace amounts of side-product were also detected in the 1 H NMR spectrum.When 5 mol % of either [Ag(PPh 3 ) 2 (κ 2 -HCO 3 )] 2 or {Ag(PPh 3 ) 2 } 2 (μ-κ, 2 κ 1 -CO 3 ) was used with Cs 2 CO 3 (0.75 equiv) as the base, the conversion improved to 98 and 99%, respectively (entries 2 and 3), and the side-product was no longer detected.With 5 mol % of Ag 2 CO 3 , the greatest conversion is 73% at 3 h, and the reaction reaches near-completion by 23 h (94% conversion) (entry 4).
Trace amounts of the homocoupling side-product were also detected.The amount of Ag used can be decreased to 2.5 mol % without an appreciable decrease in the conversion, but when 1 mol % of Ag 2 CO 3 was used, the 1 H NMR yield dropped to 80% (entries 4 and 8).The use of 10 mol % Ag(C 6 F 5 ) with 10 mol % PPh The direct arylation of 4-iodobenzene 2b with pentafluorobenzene 1 was selected as the model reaction system to be studied by HR-MAS NMR spectroscopy due to the ease of synthesis of phenyl-Pd species compared to their 4-tolyl analogues (Reaction R5).The line-broadening observed by standard NMR spectroscopy for the inhomogeneous reaction mixture was successfully resolved by the application of HR-MAS NMR spectroscopic analysis as shown in a test sample of 1, 2a, and Ag 2 CO 3 (Figure 3).
The catalyst loading was increased from catalytic (i.e., 5 mol %) to sub-stoichiometric (i.e., 0.5 equiv) to observe possible species involved in the catalytic cycle.After heating at 56 °C in the rotor, broad phenyl signals were observed that disappeared on completion of the reaction.The reaction was repeated, but this time, the probe was cooled after 20% conversion to products.The broad signals observed at δ 6.83 and 6.69 during the reaction at 56 °C in the 1 H NMR spectrum were resolved into two triplets at δ 6.91 and 6.75 at −24 °C.The carboxylic acid proton of the AcOH at δ 12.63 was also observed upon cooling.2D 1 H− 1 H COSY spectra revealed the presence of two species in the aromatic region (Figure S12).The triplet    S12).
Comparison of the phenyl resonances and the 31 P NMR signals of the Pd complexes with those of the intermediate observed during the reaction revealed that the reaction mixture contained Pd2-OAc with trace quantities of Pd1-OAc (Figure 4).Additionally, of the five Pd species analyzed, Pd2-OAc was the only complex retaining complete structural integrity after heating to 56 °C.Decomposition products such as OPPh 3 were observed for other complexes; dinuclear Pd2-OAc and Pd2-I species were observed in the 1 H and 31 P NMR spectra of mononuclear Pd1-OAc and Pd1-I complexes, respectively.
The well-resolved phenyl signals of Pd2-OAc in DMF-d 7 at 56 °C were broadened when the dinuclear complex was used as the catalyst for the reaction of 1 with 2b (Reaction R6).It is likely that Pd2-OAc is in equilibrium with Pd1-OAc.Furthermore, the use of Pd2-OAc as the catalyst for the direct arylation reaction of 2a with 1 yielded a mixture of two biaryl products in 3.5:1 ratio (3a:3b).Thus, Pd2-OAc reacted with 1 to form pentafluorophenylbenzene 3b and then catalytically turned over 2a to form the 4-(pentafluorophenyl)toluene 3a.
Whereas the reaction catalyzed by 25 mol % Pd2-OAc achieved 12% product 3b formation after 60 min, the addition of 25 mol % PPh 3 improved the yield of 3b to 25% after the same time.For the reaction with additional 75 mol % PPh 3 , 57% yield was achieved after 20 min.The addition of extra PPh 3 resulted in increased formation of species with 1 H and 31 P{ 1 H} NMR spectra very similar to those of Pd1-OAc.
Speciation in the Absence of Substrate.Recent studies have demonstrated the formation of Pd I clusters with bridging phosphide ligands in the reactions of Pd(OAc) 2 and PPh 3 in THF. 53,90We were concerned to establish whether these species are formed under the conditions of our cross-coupling reactions.We therefore examined the nature of the Pd species formed in the absence of substrates by conventional 31 P{ 1 H} NMR spectroscopy, searching for characteristic phosphide resonances in the δ 200 region.Stoichiometric reactions of Pd(OAc) 2 with PPh 3 (2 equiv) in DMF for 20 min at 60 °C with and without Ag 2 CO 3 yielded no evidence for phosphide species.There were traces of phosphide species after prolonged reaction (15 h) in the presence of Ag 2 CO 3 .Corresponding reactions in the presence of AgOAc yielded no evidence of phosphide species.The dominant product in all these reactions is OPPh 3 .

■ REACTION KINETICS
Monitoring the Reaction by IR Spectroscopy.The course of the catalytic cross-coupling reaction could be monitored by in situ IR spectroscopy.Distinctive absorption bands were identified for pentafluorobenzene, iodotoluene, and their cross-coupling product in a region where the DMF solvent does not absorb significantly (Reaction R7).The in situ FTIR spectroscopic measurements were recorded by the ReactIR with a silicon probe dipping into a stirred flask with a thermocouple measuring the temperature in the solution.An example of the reaction profiles is shown in Figure 6a for a 1:1 substrate ratio and 5 mol % Pd(OAc) 2 .To validate the method, the conversion of 4-iodotoluene 2a to biaryl product 3a was determined by integrating the methyl peaks observed by 1 H NMR analysis of aliquots sampled at regular intervals in a reaction with a 10:1 ratio of 1:2a (Figure 6b).The kinetic profiles observed by FTIR and NMR were in good agreement.The reaction exhibited no induction period and reached 50% completion in ca.6600 s and 90% completion after 15,000 s at 56 ± 1 °C under the conditions illustrated, making it clear that the temperature could be lowered and the reaction time reduced compared to the standard of Reaction R1.
Determination of the Rate Law.Detailed kinetic analysis was performed using this in situ IR approach by traditional   kinetic methods and by variable time normalization analysis (VTNA) methods.Full details of the concentrations used together with the results from the VTNA methods are given in the Supporting Information (Figures S24−S26).Here we report the results from traditional isolation methods.Initial experiments were performed with a 10-fold excess of either 1 or 2a (initial concentrations 0.018 and 0.18 M).With excess 1, the decay of 2a was linear to 50% conversion (R 2 = 0.997); with excess 2a, the decay of 1 was exponential with a linear fit to ln [1] to 50% conversion (R 2 = 0.998).These results are consistent with a reaction that is zero order in 2a and first order in 1.A more detailed analysis of the dependence of pseudo-zero-order rate constant on [1] was carried out with [1]/[2a] ranging from 10 to 50, revealing a two-term rate law with slope (2.83 ± 0.26) × 10 −6 s −1 and intercept (1.12 ± 0.10) × 10 −6 mol dm −3 s −1 (Figure 7).The rate dependence on [Pd tot /2PPh 3 ] at 56 ± 1 °C was measured between 0.19 and 3.7 mM catalyst concentration under pseudo-zeroth-order reaction conditions with a 10-fold excess of pentafluorobenzene 1 (0.18 M) to 4-iodotoluene 2a (0.018 M) (Table S14).Because the Pd(OAc) 2 /PPh 3 ratio was maintained at 1:2 for each kinetic measurements, we refer to the concentration [Pd tot /2PPh 3 ].The plot of k obs vs [Pd tot / 2PPh 3 ] 0.5 gave better correlation coefficients (Figure 8) than the plot of k obs vs [Pd tot /2PPh 3 ] 0.75 whose correlation coefficients, in turn, were much better than those for the plot of k obs vs [Pd tot /2PPh 3 ].The kinetics was measured similarly for iodobenzene 2b as substrate.The concentration of the limiting reagent 2b was increased to 55 mM (from 18 mM used for 2a) to allow for the lower peak intensities observed for 2b (at 1016 cm −1 ) and the product 3b (at 989 cm −1 ).The kinetics follows a similar pattern to that for 2a (Figures 7 and  8).
Thus, the overall rate law is given by eq 2: The values of k 1 and k 2 are estimated by dividing the slopes of Figure 7 by [Pd tot /2PPh 3 ] 0.5 (Table 5).The value of k 1 is about 3 times larger for 2b than for 2a, but the values of k 2 are very similar.Triphenylphosphine can play several roles including acting as a reducing agent for Pd(OAc) 2 , ligand for silver, and ligand for palladium.Moreover, several species may form in each role.For these reasons, we investigated the effect of the Pd/PPh 3 ratio on the reaction kinetics.At a constant 5 mol % Pd(OAc) 2 , the reaction kinetics was studied with [PPh 3 ] ranging from 5 mol % (1:1 Pd/PPh 3 ) to 40 mol % (1:8 Pd/ PPh 3 ).The rate increased linearly up to 1:4 Pd/PPh 3 but decreased slightly at higher concentrations than 1:4 and then leveled off (Figure S31).The dependence of the rate on [C 6 F 5 H] (at 0.93 mM catalyst) exhibited a very similar slope to that for 1:2 Pd/PPh 3 but a markedly larger intercept (Figure 7).The variation of the rate with [Pd tot /4PPh 3 ] was also determined (Figure S32); whereas the slope of k obs vs [Pd tot / 2PPh 3 ] 0.5 was (6.2 ± 0.7) × 10 −5 M 0.5 s −1 , that of [Pd tot / 2PPh 3 ] 0.5 was (15.6 ± 2.0) × 10 −5 M 0.5 s −1 , an increase of a factor of 2.5.The overall rate constants are given in Table 5; the most marked change is the increase in the k 1 term by a factor of 3.This change can be understood if the oxidative addition of aryl iodide precedes the rate determining step.Thus, the rate is determined by the reactivity of Pd-(PPh 3 ) n (Ar)I or related species (see below).
The reaction kinetics was also determined for a range of 4substituted iodoarenes in place of iodotoluene.Additionally, the conversions were determined in competition between 4iodotoluene and alternative 4-substituted iodoarenes.The effects of substitution were very minor (Table S22).
The kinetics of reactions in the presence of catalytic quantities of the isolated stable Pd II species studied earlier by HR-MAS NMR was monitored by in situ FTIR spectroscopic analysis (Table 6).The mononuclear and the dinuclear complexes were added in 5 and 2.5 mol % loading, respectively, to give 5 mol % Pd-atom loading per reaction.It should be noted that some thermal decomposition at 56 ± 1 °C was observed by HR-MAS NMR study for every complex except for [Pd(Ph)(μ-OAc)(PPh 3 )] 2 .The kinetic profiles and the observed rate constants for the reactions catalyzed by the dinuclear Pd complex were compared with those for the catalyst mixture of 5 mol % Pd(OAc) 2 and 10 mol % PPh 3 .Of the dinuclear Pd complexes tested, Pd-2-OAc and Pd1-OAc gave rates very close to Pd(OAc) 2 /2PPh 3 .Pd1-I was significantly faster, comparable to Pd(OAc) 2 /3PPh 3 .Pd2-OH and Pd2-I were ineffective when used alone but reached comparable rates with added AcOH.
The role of Pd-NPs in the model reaction was considered by monitoring the reaction kinetics using preformed DMFstabilized Pd-NP solution (0.9 mM).The reaction achieved 54% conversion of 1 after 40 h.In comparison, the reaction catalyzed by Pd(OAc) 2 achieved quantitative conversion of substrate in 3 h (Figure S36).The result suggested that the two reactions are catalyzed by different active species and that the Pd-NPs were much less active.
Kinetic Isotope Effect.The kinetic isotope effect was investigated by monitoring the reaction under pseudo-zerothorder kinetics with 10-fold excess (i.e., 0.18 M) of deuteropentafluorobenzene (C 6 F 5 D) 1-d at 56 ± 1 °C with Pd(OAc) 2 /2PPh 3 .The IR spectrum of 1-d was significantly different from that of C 6 F 5 H 1. The characteristic peak of 2a at 1009 cm −1 overlapped with the band of 1-d at 1007 cm −1 .However, it was possible to follow the reaction progress by observing the peak of the product 3a at 989 cm −1 .The k obs values of separate reactions of 1 and 1-d were obtained from the gradient between 20 and 80% conversion yielding k H /k D 4.36 ± 0.06 at 56 ± 1 °C (Figure 9).These measurements were repeated with a higher concentration of 1/1-d at both 56 and 40 °C, revealing a substantial reduction in KIE at higher concentrations of 1/1-d and an increase in KIE on reduction of the temperature (Table 7).The KIE was also determined with Pd/PPh 3 1:4 as 3.86 ± 0.12 at 56 ± 1 °C with a 10-fold excess  The values of the KIE reported above are derived directly from k obs and therefore represent a composite of the k 1 and k 2 terms.Because the k 1 term is independent of [1], it is expected to have a KIE of 1.0.However, close inspection of the data shows that the k 1 term is much less important for 1-d.The k 2 term is dominant at higher [1], suggesting that the true value of the KIE for this term is ∼2.30.The origin of the paradoxical behavior is probed further in the discussion.
Temperature Dependence of Rates.The temperature dependence of the rate of the catalytic reaction between 1 and 2a was studied at varying concentrations of 1 under the same conditions as in Figure 7 over the temperature range 323−345 K (Figure 10a).After conversion of the resulting slopes and intercepts to k 1 and k 2 assuming half-order in [Pd tot ], Eyring plots yielded values of ΔH ‡ and ΔS ‡ (Figure 10b).The values of ΔH ‡ for the k 1 and k 2 terms were 57.4 ± 4.8 and 57.5 ± 2.6 kJ/mol, and those for ΔS ‡ were −166 ± 15 and −157 ± 8 J/K mol.These values are the same within error, suggesting that there is a link between them; but at present, we have not identified the cause.

■ DISCUSSION
The results in this paper show that direct arylation of 4iodotoluene 2a with pentafluorobenzene 1 is effective using readily available Pd II and Pd 0 precatalysts Pd(OAc) 2 /PPh 3 , Pd(PPh 3 ) 2 Cl 2 , and Pd(PPh 3 ) 4 .The most effective bases were found to be Ag 2 CO 3 and [Me 4 N]OAc when used in conjunction with polar aprotic solvents such as DMF, DMAc, and NMP.The system with Pd(OAc) 2 /PPh 3 and Ag 2 CO 3 in DMF was studied in detail.
The first indications of the reactivity of Ag 2 CO 3 toward 1 came from H/D exchange experiments.Investigation of the reactions of PPh 3 and pentafluorobenzene with Ag 2 CO 3 showed the formation of Ag(C 6 F 5 )(PPh 3 ) n species, but lowtemperature 31 P{ 1 H} NMR revealed the presence of numerous species at equilibrium.Likewise, the previously described silver carbonate [Ag(PPh 3 ) 2 ] 2 CO 3 •2H 2 O proved highly labile and reactive toward 1 even at room temperature.[Ag(PPh 3 ) 2 (κ 2 -HCO 3 )] 2 was also reactive if Cs 2 CO 3 was added.Related species could be obtained by reaction of Ag(C 6 F 5 ) with PPh 3 .
Considering the reactivity of the silver compounds toward 1, we tested whether the standard 0.75 equiv Ag 2 CO 3 used in the catalytic reaction of 1 with 2a could be reduced to a catalytic amount.Indeed, catalytic quantities of any of Ag 2 CO 3 , [Ag(PPh 3 ) 2 ] 2 CO 3 •2H 2 O, or [Ag(PPh 3 ) 2 (κ 2 -HCO 3 )] 2 were effective if used in conjunction with Cs 2 CO 3 as substoichiometric base.These experiments indicate that the Ag 2 CO 3 /PPh 3 system is competent to activate the C−H bond of 1 in a similar way to Ag 2 CO 3 /XPhos 45 but the PPh 3 system is complicated by the extreme lability of the Ag−PPh 3 bonds.We therefore have to consider the possibility that C−H activation by Ag I competes with C−H activation by Pd II .Studies of the reactivity of 1 with iodobenzene 2b in the presence of a variety of Pd complexes and Ag 2 CO 3 by HR-MAS NMR led to the identification of [Pd(C 6 H 5 )(μ-OAc)(PPh 3 )] 2 Pd2-OAc and Pd(C 6 H 5 )(κ 1 -OAc)(PPh 3 ) 2 Pd1-OAc under high Pd(OAc) 2 concentrations.The stoichiometric reaction of the isolated Pd species Pd2-OAc with 1 at 70 °C yielded the expected coupling product 3b quantitatively, whereas the reaction of Pd1-OAc with 1 achieved 45% yield without Ag 2 CO 3 and 100% with Ag 2 CO 3 .These investigations lead to the postulate of Pd1-OAc and Pd2-OAc as likely resting states in the catalytic reaction.Other species such as Pd1-I and Pd2-I are also active but less effective than the acetate complexes.Evidently, multiple Pd species are present, and the speciation will vary with PPh 3 concentration and temperature.
We now consider the interpretation of the kinetic results.The k 2 term of the rate law (eq 2) shows that the rate depends on [C 6 F 5 H] and [Pd tot /2PPh 3 ] 0.5 , a similar rate expression to that described by Rosner et al. 91 This expression is consistent with a catalytically active mononuclear Pd 0 species that reacts rapidly with ArI to form Pd II species present in monomeric and dimeric forms.The monomer is active in the catalytic cycle, but the dimeric species with which it is at equilibrium is inactive.The concentration of the monomer is given by K eq [dimer] 0.5 , leading to the half-order dependence.The monomer proceeds to react with C 6 F 5 H and base before reductive elimination of product ensues.The small value of ΔH ‡ and the large negative ΔS ‡ are consistent with a bimolecular reaction in the rate determining transition state. 92This catalytic cycle is similar to that shown in Scheme 1a with the addition of the monomer−dimer equilibrium.It is tempting to identify the monomer and dimer as Pd1-OAc and Pd2-OAc (or their tolyl equivalents) that were identified as resting states through the HR-MAS NMR experiments.The value of k 2 is little changed when using a 4:1 ratio of [PPh 3 ]/ [Pd(OAc) 2 ] in place of a 2:1 ratio, indicating that the Pd II speciation is little affected by this change.The significant KIE (∼2.30 taken from the higher [1] at 56 °C) and substantial entropy of activation are consistent with this model.There are several indications that this model of the k 2 reaction may be oversimplified and that multiple species contribute.First, the experiments with carbonate complexes of silver show that multiple complexes of Ag I with PPh 3 and carbonate are present and could be active as bases; second, the HR-MAS NMR experiments show the presence and activity of several Pd II species.The variation of the KIE with reaction conditions is a likely consequence of the complex speciation.
The k 1 term of the rate law shows dependence on [Pd tot / 2PPh 3 ] 0.5 and is increased by a factor of ∼2.5 with a 4:1 ratio of PPh 3 to Pd tot .The absence of a dependence on [C 6 F 5 H] is consistent with C−H activation of 1 by Ag I (PPh 3 ) n followed by transmetalation to any of Pd1-OAc, Pd2-OAc, Pd1-I, or Pd2-I.The dependence on [Pd tot /2PPh 3 ] 0.5 indicates that the monomer−dimer equilibrium remains important and that the rate-determining transition state is likely to be associated with the transmetalation and/or reductive elimination.Considering the negative value of ΔS ‡ and small value of ΔH ‡ , transmetalation is more likely.Direct participation of the solvent could also be possible.The dependence on [PPh 3 ] is consistent with the requirement for sufficient ligand to solubilize the Ag 2 CO 3 and activate 1; the concentrations of PPh 3 are suboptimal at the lower ratio because PPh 3 is consumed both by reduction of Pd II to Pd 0 with formation of OPPh 3 and by coordination to Ag I .To understand the variation of KIE with conditions, we recall that the KIE for the stoichiometric reaction of [Ag(Xphos)] 2 (μ-κ, 2 κ 2 -CO 3 ) with pentafluorobenzene is 3.7 ± 0.3, a value that we may assume is close to that for PPh 3 analogues.This value would mean that the k 1 term is slowed more than the k 2 term by deuteration, and we postulate that the Ag I route to C−D activation is uncompetitive with the Pd II route.Unfortunately, we cannot monitor the rate of C−H/C−D activation by Ag(PPh 3 ) n species because of their lability and the consequent multiple speciation.The similarity of the rate constants for different catalysts Pd(OAc) 2 /nPPh 3 , Pd(PPh 3 ) 4 , Pd-2OAc, Pd1-OAc, and Pd1-I points to common mechanisms.We anticipate that the catalytic mechanism involving bond activation by Ag I is similar to that shown in Scheme 1b with the proviso of multiple speciation of both silver and palladium complexes that vary with conditions.

■ CONCLUSIONS
The direct arylation of iodoarenes by pentafluorobenzene 1 is a prototype reaction that is catalyzed by palladium complexes in the presence of triphenylphosphine and silver carbonate.The reaction is typically performed with 0.75 equiv Ag 2 CO 3 , but the use of Ag 2 CO 3 may be reduced to catalytic quantities in the presence of Cs 2 CO 3 .The simplicity of the components does not mean, however, that the reaction mechanism is straightforward.Our study has demonstrated a Pandora's flask of multiple species that can only be interpreted through previous research on the reactivity of analogous systems using phosphines such as XPhos.Both in situ IR spectroscopy and high-resolution magic angle spinning NMR spectroscopy proved useful in our analysis, in addition to solution NMR methods.We have shown that the reaction of Ag 2 CO 3 with PPh 3 and 1 leads to C−H bond activation with multiple Ag complexes present in solution.The same applies when starting with isolated complexes such as [Ag(PPh 3 ) 2 ] 2 CO 3 •2H 2 O.−43 The problem of multiple speciation also applies to the palladium complexes, although it is not so acute.Our HR-MAS experiments point to [Pd(Ar)(μ-OAc)(PPh 3 )] 2 and Pd(Ar)(κ 1 -OAc)(PPh 3 ) 2 (Ar = Ph, 4-tolyl) as likely resting states that are at equilibrium, with the dimer as the major species.The reaction kinetics studied by in situ IR spectroscopy demonstrates that synthetic experiments may be performed with a 1:1 ratio of [ArI]/[C 6 F 5 H] under milder conditions (56 °C, 5 h) than are typically used (70 °C, 24 h).Rates are improved with Pd(OAc) 2 + 4PPh 3 or Pd(PPh 3 ) 4 compared with the standard Pd(OAc) 2 + 2PPh 3 in keeping with the multiple roles of PPh 3 for coordination of both Ag and Pd, as well as reduction of Pd(OAc) 2 .Higher [PPh 3 ] also favors monomeric Pd complexes over dimeric complexes.Similar rate constants are found with [Pd(Ph)(μ-OAc)-(PPh 3 )] 2 and Pd(Ph)(κ 1 -OAc)(PPh 3 ) 2 as catalysts.A twoterm rate law is found with both terms dependent on [Pd tot / 2PPh 3 ] 0.5 , consistent with an off-cycle Pd dimer dissociating to form an on-cycle Pd monomer.The k 1 term is independent of [1], whereas the k 2 term is first order in [1].Neither term shows dependence on [ArI].We interpret the k 1 term as arising from C−H bond activation by Ag I , whereas the k 2 term Organometallics involves C−H activation by Pd II .Both processes require baseassistance and may proceed by AMLA/CMD mechanisms.The multiple speciation of both Ag I (PPh 3 ) and Pd II (PPh 3 ) complexes leads to a situation where it is no longer appropriate to define a mechanism in full.In particular, the implications of the extraordinary lability of Ag I (PPh 3 ) species have not been recognized previously.Thus, a reaction with apparently wellbehaved kinetics disguises extraordinary complexity.It may be possible to suppress C−H bond activation by one of Pd II or Ag I by adding appropriate inhibitors. 49ASSOCIATED CONTENT * sı Supporting Information The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.organomet.3c00309.
General information on chemicals and instruments, general procedures, synthetic procedures and compound data, studies on conversion, speciation of silver complexes, analysis of catalytic intermediates by HR-MAS NMR spectroscopy, and reaction kinetics by in situ IR spectroscopy (PDF) ■ AUTHOR INFORMATION Corresponding Authors Scheme 1.(a) Commonly Proposed CMD/AMLA(6) Mechanism for Direct Arylation of Pentafluorobenzene.(b) Catalytic Cycle with Silver Performing C−H Activation Step (Adapted with Permission from ref 45, Copyright 2022, American Chemical Society) 5 equiv [Me 4 N][OAc] or with Pd(OAc) 2 + 10 mol % PPh 3 + 0.75 equiv Ag 2 O. Changing the base to any of K 2 CO 3 , Cs 2 CO 3 , AgOAc, or [Bu 4 N][OAc] resulted in marked reductions in yields.A recent paper reports H/D exchange of pentafluorobenzene with 10 mol % Cs 2 CO 3 in d 6 -acetone or d 6 -DMSO. 74Some of the action of bases that we observe may be caused by deprotonation of C 6 F 5 H. Nevertheless, only [Me 4 N]OAc and Ag 2 CO 3 give full conversion in the catalytic reaction.

aFigure 1 .
Figure 1.Hammett plot of the competition reaction shown in Reaction R2.
3 and Cs 2 CO 3 (0.75 equiv) resulted in almost identical conversion (entry 9) to the experiments with other Ag complexes.These reactions demonstrate that the conversion can be increased to well above 90% by combining sub-stoichiometric Cs 2 CO 3 with catalytic quantities of any of Ag 2 CO 3 , [Ag(PPh 3 ) 2 (κ 2 -HCO 3 )] 2 , [Ag(PPh 3 ) 2 ] 2 CO 3 , or Ag-(C 6 F 5 ), thus eliminating the need for large quantities of silver salts.Pd Speciation: Studies by HR-MAS and Conventional NMR.Identification of Catalytic Resting States.

Figure 3 .
Figure 3. 1 H NMR spectra of a mixture of 1, 2a, and silver carbonate in DMF-d 7 at 13 °C (a) without spinning and (b) spinning at 3 kHz.

Table 1 .
Conversions of 2a and Yields of Isolated Product 3a

Table 2 .
Stoichiometric Reaction of PPh 3 -Coordinated Ag Complexes and C 6 F 5 H a a 10 equiv C 6 F 5 H. b Detected by the ortho-F resonances at δ −106.0.

Table 3 .
Influence of Catalytic Amounts of Ag Salts and Complexes on Direct Arylation

Table 4 .
NMR Yields of 3b from Stoichiometric Reactions of Pd Species and 1 in DMF a Conditions as shown in Scheme 4 other than base.b Based on integration of C 6 F 6 (internal standard) and 3,5-fluorines of 3a and 3b. a

Table 6 .
19served Rate Constants for the Direct Arylation Reaction of 1 with 2a Catalyzed by Isolated Pd Species Change in the concentration of product 3a over time for the reaction of 2a with 10-fold excess of (black) C 6 F 5 H 1 and (red)C 6 F 5 D 1-d.[Catalyst] 5 mol % wrt 2a: 0.92 mM, [PPh 3 ] 1.8 mM, [1]180 mM, [2a] 18 mM.Ag 2 CO 3 0.75 equiv, temp 56 ± 1 °C.A control reaction showed that no formation of 1 occurred according to 1 H and19F NMR spectroscopy under the standard reaction conditions when the direct arylation was carried out with 1-d, showing that the C−H bond activation step is irreversible.Exchange does occur, however, with 1 in the presence of D 2 O and Ag 2 CO 3 and PPh 3 as described above.