Elucidating the reaction mechanism of a palladium-palladium dual catalytic process through kinetic studies of proposed elementary steps

Mechanistic analysis of catalytic reactions is typically performed under synthetically relevant conditions using kinetic tools such as RPKA and VTNA. However, for reactions involving multiple interconnected catalytic cycles—such as synergistic dual catalysis where both partners are activated in situ—the mechanistic pathway is challenging to elucidate with conventional methods. The copper-free Sonogashira (Heck–Cassar) coupling of aryl halides with terminal alkynes is a prime example. Historically, a monometallic mechanism (akin to Heck or Buchwald–Hartwig) without transmetallation was proposed. Yet, experimental and computational studies have not unambiguously confirmed this pathway. The authors recently proposed an alternative involving two distinct Pd catalytic cycles connected by a Pd–Pd transmetallation step, placing the copper-free Sonogashira within bimetallic catalysis executed by a single metal. The present study aims to dissect this mechanism into elementary steps using independently prepared intermediates to determine relative rates, identify the rate-determining step (RDS), and clarify how and when each reagent enters the cycles, thereby enabling rational optimization of such dual catalytic processes.

The Sonogashira reaction classically employs Pd/Cu co-catalysis; copper-free variants were reported by Cassar and Heck (1975). Copper co-catalysis improves efficacy but introduces drawbacks (environmental concerns, homocoupling, O2 sensitivity), motivating copper-free methods. A monometallic Pd mechanism for copper-free Sonogashira was widely postulated and supported by several experimental and theoretical efforts (trapping studies, competition experiments, labeled MS studies), though not conclusively. The authors previously advanced a Pd–Pd dual catalytic hypothesis (two Pd cycles linked by Pd–Pd transmetallation), aligning with a limited set of prior Pd–Pd bimetallic reports (e.g., arylation of pyridine N-oxide, cyanation with HCN, aerobic oxidative arene coupling, carbonylative Sonogashira). Prior mechanistic dissections have sometimes isolated key steps (OA, TM, RE), but comprehensive disassembly and independent kinetic analysis for a synergistic bimetallic process as done here are rare.

The proposed mechanism was deconstructed into two Pd cycles and further into elementary steps: (i) oxidative addition (OA) to form trans-Pd(PPh3)2(Ar)(X) (complexes 7), (ii) Pd–Pd transmetallation between Pd bisacetylides and Pd aryl halide OA complexes, culminating in reductive elimination (RE) to product, and (iii) organometallic nucleophile (re)formation (ONF) to generate palladium bisacetylides (complexes 6) from monoacetylides (5) or from Pd(II) halide precursors (Pd(PPh3)2X2) and terminal alkynes under base. - Synthesis of mimics for D (monoacetylides 5): Oxidative addition of haloalkynes (iodo-, bromo-, chloro-alkynes) to Pd(PPh3)4 in benzene at RT provided trans-Pd(PPh3)2(CCR)(X) (5a–k, etc.) in 19–81% isolated yields. Complexes characterized by IR, HRMS, 1H/13C/31P NMR; solutions stable for ~1 h at RT in CDCl3, solids stable ~7 days at −20 °C under Ar. - Formation of bisacetylides C (6) by two routes (mimicking ONF): Method A (regeneration from D): 5 + alkyne 2, NaOH/MeOH, RT, giving trans-Pd(PPh3)2(CCR1)(CCR2) (6) in 28–95% yields (halide X = I/Br/Cl showed little influence). Method B (initial formation from PdII): Pd(PPh3)2X2 + alkyne 2, NaOH/MeOH, RT, providing 6 in 27–93% yields; simple filtration sufficed for isolation. Unsymmetrical 6 prepared via OA to form 5 followed by halide substitution. - Preparation of OA complexes A (7): trans-Pd(PPh3)2(Ar)(X) synthesized by OA of aryl halides (X = I, Br, Cl, OAc) to Pd(PPh3)4. For tricoordinate surrogates, Pd(P(o-tolyl)3)(4-MeC6H4)(I) (7a′) was used to mimic reactive Pd(PPh3)(Ar)(X) species present under catalytic conditions in amine base. - Transmetallation studies (TM + RE): Stoichiometric reactions between 6 and 7 were conducted in CDCl3 at 298–302 K with concentrations ~0.01 M (matching catalytic Pd loadings). 31P NMR monitored concentration-time profiles; conversions quantified by 1H NMR using 1,3,5-trimethoxybenzene as internal standard. Solvent comparisons supported CDCl3 as optimal for monitoring. - Kinetic comparisons of elementary steps vs catalysis: Model substrates 4-iodotoluene (1a) and phenylacetylene (2a) were used. Catalysis employed Pd(PPh3)2I2 precatalyst (10 mol%), CH2Cl2 solvent, pyrrolidine base; OA monitored with Pd(PPh3)4; TM/RE monitored with 6a and 7 or 7a′. Reaction rates compared under similar concentrations (0.01 M in Pd-containing species) and ambient temperature (~296–302 K). - Traditional kinetic and VTNA analyses under catalytic conditions determined empirical orders by varying initial concentrations and analyzing maximum rates (ln–ln slope) and VTNA plots. - Halide/pyrrolidine speciation studies: Added Bu4NCl to probe in situ halide metathesis effects on rates and speciation. Equilibria of pyrrolidine binding to 7 (7 ↔ 7′(pyr.)) and to 5 were quantified by 31P NMR. Chloride-induced halide exchange in 7 and 5 was assessed. Effect of chloride/pyrrolidine on 6 assessed (none observed by 31P NMR). - Electronic effects: Hammett analyses for TM reactions with para-substituted aryl groups in 7 and varied substituents on the alkynyl ligands in 6, plotting log relative rates vs σ parameters.

- Pd–Pd mechanism supported: Independently prepared Pd bisacetylides (6) react with Pd aryl halide OA complexes (7) to give product rapidly under relevant conditions, consistent with a Pd–Pd transmetallation pathway in the copper-free Sonogashira reaction. - Rate-determining step (RDS) under model conditions (4-iodotoluene 1a, phenylacetylene 2a, Pd(PPh3)2I2, pyrrolidine, CH2Cl2, RT): Formation of Pd bisacetylide 6a from monoacetylide 5a and 2a (ONF) matches the catalytic rate and is identified as the likely RDS. OA of 1a to Pd(0) is instantaneous; TM/RE between 6 and 7 is fast under many conditions but can be slower with unstable tricoordinate surrogates. - Kinetic orders (catalysis): Traditional kinetic analysis gave orders of ~1.0 in Pd, −0.1 in aryl iodide, 1.1 in pyrrolidine, and 0.3 in phenylacetylene. VTNA yielded ~1.2 in Pd, 0 in aryl iodide, 1.1 in pyrrolidine, and 0.4 in phenylacetylene. These support an RDS within the multistep formation of 6a from 5a. - Comparative rates with halide additives (296 K, CH2Cl2, pyrrolidine): Reaction rate increased from 34.37 µmol/L·s with Pd(PPh3)2I2 (no additive) to 53.75 µmol/L·s with Pd(PPh3)2Cl2 (no additive). Addition of Bu4NCl to the Pd(PPh3)2I2 system accelerated rates to 78.48 µmol/L·s (0.2 eq) and 101.86 µmol/L·s (1.1 eq), indicating in situ halide metathesis can accelerate the overall process, correlating with faster TM. - Speciation effects: Chloride effects include instantaneous halide exchange in 7a (I → Cl) and in 5a (I → Cl), while 6a is unaffected by Cl− or pyrrolidine by 31P NMR. Pyrrolidine forms equilibria with 7 (K ≈ 0.15 for 7a, 0.34 for 7g) and with 5 (K ≈ 0.03 for 5a, 0.08 for 5c), decreasing the effective order in 7 during TM (observed order: 1 in 6a, ~0.5 in 7a in presence of pyrrolidine). - Hammett analysis: Electronic substituents modulate TM/RE rates. Para-electron-withdrawing substituents on the aryl of 7 increase rates (positive ρ ≈ +0.48 to +0.53), while electron-donating substituents on the alkynyl ligands in 6 tend to increase rates (negative ρ ≈ −0.38 to −0.42), consistent with a multistep Pd–Pd TM mechanism sensitive to ligand electronics. - Mechanistic picture of TM: Data support a multistep process likely involving PPh3 dissociation from 7 to form a cyclic Pd–Pd intermediate with bridging iodo/alkynyl ligands, followed by dissociation to monoacetylide and RE. Dissociation of the Pd–Pd complex (or RE) may be rate-limiting for TM. Observed halide reactivity order in 7 for TM: Cl > Br > I, rationalized by Pd–X bond strengths and trans effects.

Disassembly of the copper-free Sonogashira mechanism into isolable intermediates enabled direct kinetic comparison of elementary steps. The findings substantiate a Pd–Pd dual catalytic manifold where a Pd bisacetylide interacts with a Pd aryl halide complex via transmetallation to form the cross-coupled product. Under the model conditions (aryl iodide substrate), OA is rapid and not rate-limiting. The ONF step regenerating/producing Pd bisacetylide from monoacetylide aligns with the catalytic rate and emerges as the RDS, explaining the induction period observed when starting from terminal alkyne and base. Electronic and halide effects observed in TM corroborate a multistep pathway requiring PPh3 dissociation and formation of Pd–Pd bridged intermediates, with chloride promoting faster processes. The agreement between stoichiometric and catalytic rates (despite known differences in speciation under catalytic turnover) supports the validity of the stepwise kinetic approach. These insights are directly relevant for reaction optimization: tuning base, halide environment, and ligand electronics can modulate the rate-limiting ONF and the TM step, enabling balanced kinetics across the two Pd cycles for improved performance. The results also rationalize how different aryl halides (e.g., bromides or chlorides) or ligand sets could shift the RDS (e.g., to OA), highlighting the importance of substrate/ligand choices in mechanistic regime control.

The study provides experimental mechanistic insight into a one-metal dual catalytic process for the copper-free Sonogashira reaction by deconstructing the catalytic manifold into elementary Pd-mediated steps and measuring their kinetics independently. Palladium bisacetylides were synthesized and leveraged as key mechanistic tools, revealing a Pd–Pd transmetallation pathway and establishing, for the 4-iodotoluene/phenylacetylene system, that bisacetylide formation from monoacetylide is the rate-determining step under the chosen conditions. Electronic (Hammett) analyses and halide/pyrrolidine speciation studies clarified how ligands and halide ions tune the rates, with chloride accelerating catalysis via in situ halide metathesis. The approach demonstrates balanced kinetics between the two Pd cycles and offers a blueprint for rational optimization of synergistic bimetallic mechanisms. Future work should: (i) extend this methodology to different ligand sets and catalysts, (ii) explore diverse aryl halides/alkynes to map conditions where OA or TM/RE become rate-limiting, (iii) further resolve transient Pd–Pd intermediates and dissociation/RE steps, and (iv) integrate spectroscopic and computational tools to generalize design principles for single-metal dual catalytic systems.

- Identification of a single RDS is challenging in this complex, multistep system with equilibria; under different substrates, ligands, or conditions, another step (e.g., OA or TM/RE) may become rate-limiting. - Stoichiometric model reactions differ from catalytic turnover environments; speciation and side reactions can diverge, potentially affecting rate comparisons. - The tricoordinate OA surrogate 7a′ is unstable (aryl scrambling/side reactions), likely underestimating intrinsic TM/RE rates in those experiments. - Significant influence of amine base and halide on speciation complicates traditional kinetic interpretations (e.g., decreased order in 7 due to amine binding), potentially masking TM as RDS in some analyses. - Generalizability across broader substrate classes and ligand frameworks remains to be validated.