Understanding the reaction mechanisms of catalytic processes is crucial for optimizing and designing efficient reactions. Synergistic dual catalysis, involving two interconnected catalytic cycles, poses a significant challenge for mechanistic elucidation. Traditional methods like RPKA and VTNA often prove insufficient for such complex systems. This study focuses on the copper-free Sonogashira reaction (Heck-Cassar alkynylation), a palladium-catalyzed cross-coupling reaction between aryl halides and terminal alkynes, which has been previously suggested to proceed via a monometallic mechanism or a bimetallic mechanism involving two distinct palladium cycles. The existing literature offers various mechanistic proposals, supported by experimental and theoretical studies, but lacks a conclusive understanding. Previous experimental work using synthetically relevant conditions, including intermediate trapping and competitive studies, failed to unambiguously confirm any specific mechanism. A recent proposal suggests a bimetallic mechanism, where one palladium catalyst activates the aryl halide and another activates the terminal alkyne, linked via a palladium-palladium transmetallation step. This study aims to test this bimetallic hypothesis using a novel approach—deconstructing the proposed mechanism into elementary steps, preparing the proposed intermediates independently, and studying their kinetics. This strategy allows for a detailed kinetic analysis of each step, enabling the identification of the rate-determining step and offering deeper mechanistic insights into this complex reaction.

Palladium-catalyzed cross-coupling reactions are fundamental tools in organic synthesis. The Sonogashira reaction, utilizing palladium and copper catalysts, is a seminal example of synergistic dual catalysis. However, the copper-free variant, independently described by Cassar and Heck, offers advantages by avoiding environmentally unfriendly reagents and undesirable byproducts. While a monometallic mechanism has been initially proposed, analogous to the Heck reaction and Buchwald-Hartwig amination, several experimental and theoretical studies have raised questions regarding its validity. Several studies investigated the reaction under synthetically relevant conditions but could not definitively confirm the mechanistic pathway. The proposed bimetallic mechanism, where two palladium catalysts independently activate the substrates, is a less common but compelling alternative, yet requires rigorous investigation. Few reports postulate this type of palladium-palladium dual catalysis, focusing primarily on systems such as arylation of pyridine N-oxide, cyanation of aryl bromides, aerobic oxidative coupling of arenes, and carbonylative Sonogashira cross-coupling. These previous studies highlight the complexity of multi-cycle catalytic reactions and the need for novel approaches to mechanistic analysis.

The research employed a unique mechanistic approach. The proposed bimetallic mechanism for the copper-free Sonogashira reaction was divided into elementary steps, allowing for independent kinetic studies. Key intermediates, namely palladium monoacetylides (mimicking intermediate D) and palladium bisacetylides (mimicking intermediate C), were synthesized independently using modified literature procedures. Palladium monoacetylides (5) were prepared in moderate to good yields (19–81%) by reacting various iodoalkynes, bromoalkynes, and chloroalkynes with Pd(PPh3)4 in benzene. These intermediates were characterized using IR, HRMS, and NMR spectroscopy. Notably, they were relatively stable (approximately 1 hour at room temperature in CDCl3) and could be stored under inert conditions. Palladium bisacetylides (6) were synthesized using two methods: Method A involved a base-mediated reaction of monoacetylides (5) with alkynes (2), mimicking the regeneration pathway in the catalytic cycle. Method B employed a base-mediated reaction between the alkyne (2) and LPdX2, a palladium source that mirrors the initial acetylide formation in catalysis. Symmetrical and unsymmetrical bisacetylides were successfully prepared, characterized, and employed as defined reaction components. Oxidative addition complexes (7), mimics of intermediate A, were also prepared. The synthesis and characterization of these key intermediates facilitated investigation of the elementary reactions of the catalytic cycle. Transmetallation reactions were directly monitored by reacting synthesized palladium bisacetylides (6) with palladium oxidative addition complexes (7). Concentration-time plots, coupled with 31P NMR spectra, were used to follow the reaction progress. The conversion into the tolan product (3) was determined using 1H NMR analysis. These reactions were performed under various conditions to examine the effect of different halide ligands (Cl, Br, I) and substituents on the alkynes. Kinetic studies of the elementary steps (oxidative addition, transmetallation, and reductive elimination) were performed to identify the rate-determining step by comparing reaction rates under similar conditions. Traditional kinetic analysis, determining the order of each reactant and catalyst, and VTNA analysis were conducted for a more thorough evaluation. Additionally, experiments were performed to investigate the influence of added chloride ions and the coordinating base pyrrolidine on the palladium species formed. These studies clarified the role of chloride in accelerating the catalytic reaction and explored halide metathesis as a potentially influential factor.

This research provides several key findings. First, palladium bisacetylides, previously undescribed in cross-coupling catalysis, were synthesized and fully characterized. These compounds proved essential for mechanistic analysis, providing defined reagents for studying transmetallation. The synthesis of both symmetrical and unsymmetrical palladium bisacetylides was achieved using two distinct methods, demonstrating a general and simple route to these previously elusive intermediates. These synthetic methods allowed for precise control over the reaction conditions and facilitated the investigation of the elementary steps in the catalytic cycle. Secondly, stoichiometric transmetallation reactions between independently synthesized palladium bisacetylides (6) and palladium oxidative addition complexes (7) were studied in detail. Hammett plots were generated from these data, giving further insight into the electronic effects of substituents on the alkynyl and aryl ligands during transmetallation. These plots indicated a positive correlation between the electron-donating ability of the alkynyl substituent and the rate of transmetallation, suggesting electron density plays a crucial role in this step. Conversely, a negative correlation was observed between electron-withdrawing aryl substituents and the rate of transmetallation. Thirdly, the kinetic studies of the elementary steps, compared under identical conditions, revealed balanced kinetics for the two palladium cycles. The rate of formation of the palladium bisacetylide (6) from the palladium monoacetylide (5) proved to be the rate-determining step of the overall catalytic reaction, as validated through both traditional kinetic analysis and VTNA. The orders of reactants obtained from these analyses further supported the proposed rate-determining step. This finding contrasts with previous suggestions highlighting oxidative addition as the rate-determining step in similar systems. Fourthly, the influence of chloride ions was investigated. The addition of chloride ions accelerated the catalytic reaction considerably, suggesting a strong impact on palladium speciation. This acceleration is correlated with the increased rate of transmetallation in the presence of chloride, although the specific mechanism of chloride involvement needs further study. Furthermore, the study demonstrated that coordinating amines, like pyrrolidine, influence palladium speciation by forming equilibrium complexes, which can affect the observed reaction order. The addition of pyrrolidine leads to a decrease in the order of the palladium oxidative addition complex (7a) in the transmetallation reaction, emphasizing the complex interplay of ligands and their effects on the reaction kinetics.

The findings of this study significantly advance the understanding of the copper-free Sonogashira reaction. The identification of palladium bisacetylide formation as the rate-determining step provides a critical insight into the reaction mechanism, challenging previous assumptions focusing on oxidative addition. The detailed kinetic analysis, involving both traditional kinetic analysis and VTNA, robustly supports this conclusion. The observed effects of added chloride ions and coordinating amines highlight the importance of palladium speciation in influencing reaction kinetics. The results strongly suggest a bimetallic mechanism involving two palladium catalysts, in contrast to the simpler monometallic models previously proposed. The balanced kinetics of the two palladium catalytic cycles indicate a finely tuned interplay between the two cycles, essential for the success of the synergistic dual catalytic process. These insights are crucial for designing and optimizing the reaction, for example through judicious selection of precatalysts and reaction conditions. The detailed mechanistic understanding provides valuable guidance for future development of similar cross-coupling reactions and other synergistic dual catalytic processes.

This research presents a comprehensive experimental mechanistic analysis of a unique palladium-palladium dual catalytic process in the copper-free Sonogashira reaction. The study introduces palladium bisacetylides as key intermediates and reveals palladium bisacetylide formation as the rate-determining step in the reaction of 4-iodotoluene and phenylacetylene. The influence of chloride ions and coordinating amines on reaction kinetics further enhances our understanding of this complex system. Future research directions could involve exploring other substrates to assess the generality of these findings. Investigating the influence of various ligands and reaction conditions on the relative rates of the elementary steps will also provide further insight. Expanding the investigation to other types of synergistic dual catalysis using single metals could lead to broader understanding of this reaction type.

While the study provides significant mechanistic insights, some limitations exist. The stability of the synthesized intermediates, particularly palladium monoacetylides, may limit the direct comparison of reaction rates under precisely identical conditions. The complexity of the system, with multiple equilibrium species present in the reaction mixture, introduces challenges in fully isolating and accounting for the various contributions. The study focused on specific substrates (4-iodotoluene and phenylacetylene), and further research is necessary to confirm the generality of these findings for other aryl halides and alkynes. Finally, the effect of chloride and pyrrolidine on palladium speciation is complex and requires more detailed investigations to fully unravel the complete picture.