Mechanochemistry-Directed Ligand Design: Development of a High-Performance Phosphine Ligand for Palladium-Catalyzed Mechanochemical Organoboron Cross-Coupling.

Mechanochemical synthesis that uses transition-metal catalysts has attracted significant attention due to its numerous advantages, including low solvent waste, short reaction times, and the avoidance of problems associated with the low solubility of starting materials. However, even though the mechanochemical reaction environment is largely different from that of homogeneous solution systems, transition-metal catalysts, which were originally developed for use in solution, have been used directly in mechanochemical reactions without any molecular-level modifications to ensure their suitability for mechanochemistry. Alas, this has limited the development of more efficient mechanochemical cross-coupling processes. Here, we report a conceptually distinct approach, whereby a mechanochemistry-directed design is used to develop ligands for mechanochemical Suzuki-Miyaura cross-coupling reactions. The ligand development was guided by the experimental observation of catalyst deactivation via the aggregation of palladium species, a problem that is particularly prominent in solid-state reactions. By embedding the ligand into a poly(ethylene glycol) (PEG) polymer, we found that phosphine-ligated palladium(0) species could be immobilized in the fluid phase created by the PEG chains, preventing the physical mixing of the catalyst into the crystalline solid phase and thus undesired catalyst deactivation. This catalytic system showed high catalytic activity in reactions of polyaromatic substrates close to room temperature. These substrates usually require elevated temperatures to be reactive in the presence of catalyst systems with conventional ligands such as SPhos. The present study hence provides important insights for the design of high-performance catalysts for solid-state reactions and has the potential to inspire the development of industrially attractive, almost solvent-free mechanochemical cross-coupling technologies.

Solid-state cross-coupling reactions of insoluble aryl halides under polymer-assisted grinding conditions.

In this study, polymer-assisted grinding (POLAG), a ball-milling technique based on the use of polymer additives, was applied to mechanochemical solid-state Suzuki-Miyaura cross-coupling reactions of insoluble aryl halides. We found that the efficiency of this challenging solid-state cross-coupling was improved by the addition of polytetrafluoroethylene (PTFE) as a POLAG additive under high-temperature ball-milling conditions. Our results suggest that POLAG is a promising approach for controlling the reactivity of insoluble substrates that are barely reactive under conventional solution-based conditions.

Dual Nickel(II)/Mechanoredox Catalysis: Mechanical-Force-Driven Aryl-Amination Reactions Using Ball Milling and Piezoelectric Materials.

The combination of a nickel(II) catalyst and a mechanoredox catalyst under ball-milling conditions promotes mechanical-force-driven C-N cross-coupling reactions. In this nickel(II)/mechanoredox cocatalyst system, the modulation of the oxidation state of the nickel center, induced by piezoelectricity, is used to facilitate a highly efficient aryl-amination reaction, which is characterized by a broad substrate scope, an inexpensive combination of catalysts (NiBr2 and BaTiO3 ), short reaction times, and an almost negligible quantity of solvents. Moreover, this reaction can be readily up-scaled to the multi-gram scale, and all synthetic operations can be carried out under atmospheric conditions without the need for complicated reaction setups. Furthermore, this force-induced system is suitable for excitation-energy-accepting molecules and poorly soluble polyaromatic substrates that are incompatible with solution-based nickel(II)/photoredox cocatalysts.

Palladium-catalyzed solid-state borylation of aryl halides using mechanochemistry.

This study describes the solid-state palladium-catalyzed cross-coupling between aryl halides and bis(pinacolato)diboron using ball milling. The reactions were completed within 10 min for most aryl halides to afford a variety of synthetically useful arylboronates in high yields. Notably, all experimental operations could be performed in air, and did not require the use of large amounts of dry and degassed organic solvents. The utility of this method was further demonstrated by gram-scale synthesis under solvent-free, mechanochemical conditions.

Tackling Solubility Issues in Organic Synthesis: Solid-State Cross-Coupling of Insoluble Aryl Halides.

Conventional organic synthesis generally relies on the use of liquid organic solvents to dissolve the reactants. Therefore, reactions of sparingly soluble or insoluble substrates are challenging and often ineffective. The development of a solvent-independent solid-state approach that overcomes this longstanding solubility issue would provide innovative synthetic solutions and access to new areas of chemical space. Here, we report extremely fast and highly efficient solid-state palladium-catalyzed Suzuki-Miyaura cross-coupling reactions via a high-temperature ball-milling technique. This solid-state protocol enables the highly efficient cross-couplings of insoluble aryl halides with large polyaromatic structures that are barely reactive under conventional solution-based conditions. Notably, we discovered a new luminescent organic material with a strong red emission. This material was prepared via the solid-state coupling of Pigment violet 23, a compound that has so far not been involved in molecular transformations due to its extremely low solubility. This study thus provides a practical method for accessing unexplored areas of chemical space through molecular transformations of insoluble organic compounds that cannot be carried out by any other approach.

Selective Mechanochemical Monoarylation of Unbiased Dibromoarenes by in Situ Crystallization.

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of liquid, unbiased dibromoarenes under mechanochemical conditions selectively afford the monoarylated products. The lower reactivity of the crystalline monoarylated products relative to the liquid starting materials should be attributed predominantly to the low diffusion efficiency of the former in the reaction mixture, which results in a selective monoarylation. The present study sheds light on a novel approach using in situ phase transitions in solids to design selective organic transformations that are difficult to achieve via conventional solution-based synthesis.

Solid-state mechanochemical cross-coupling of insoluble substrates into insoluble products by removable solubilizing silyl groups: uniform synthesis of nonsubstituted linear oligothiophenes.

Conventional solution-based organic reactions that involve insoluble substrates are challenging and inefficient. Furthermore, even if the reaction is successful, the corresponding products are insoluble in most cases, making their isolation and subsequent transformations difficult. Hence, the conversion of insoluble compounds into insoluble products remains a challenge in practical synthetic chemistry. In this study, we showcase a potential solution to address these solubility issues by combining a mechanochemical cross-coupling approach with removable solubilizing silyl groups. Our strategy involves solid-state Suzuki-Miyaura cross-coupling reactions between organoboron nucleophiles bearing a silyl group with long alkyl chains and insoluble polyaromatic halides. The silyl group on the nucleophile can act as a solubilizing group that enables product isolation via silica gel column chromatography and can be easily removed by the addition of fluoride anions to form the desired insoluble coupling products with sufficient purity. Furthermore, we demonstrate that after aromatic electrophilic bromination of the desilylated products, sequential solid-state cross-coupling of the obtained insoluble brominated substrates, followed by desilylation, afforded further π-extended functional molecules. Using this conceptually new protocol, we achieved the first uniform synthesis of the longest nonsubstituted linear insoluble 9-mer oligothiophene.

Efficient access to materials-oriented aromatic alkynes via the mechanochemical Sonogashira coupling of solid aryl halides with large polycyclic conjugated systems.

Sonogashira coupling represents an indispensable tool for the preparation of organic materials that contain C(sp)-C(sp2) bonds. Improving the efficiency and generality of this methodology has long been an important research subject in materials science. Here, we show that a high-temperature ball-milling technique enables the highly efficient palladium-catalyzed Sonogashira coupling of solid aryl halides that bear large polyaromatic structures including sparingly soluble substrates and unactivated aryl chlorides. In fact, this new protocol provides various materials-oriented polyaromatic alkynes in excellent yield within short reaction times in the absence of bulk reaction solvents. Notably, we synthesized a new luminescent material via the mechanochemical Sonogashira coupling of poorly soluble Vat Red 1 in a much higher yield compared to those obtained using solution-based conditions. The utility of this method was further demonstrated by the rapid synthesis of a fluorescent metal-organic framework (MOF) precursor via two sequential mechanochemical Sonogashira cross-coupling reactions. The present study illustrates the great potential of Sonogashira coupling using ball milling for the preparation of materials-oriented alkynes and for the discovery of novel functional materials.

Mechanochemical synthesis of magnesium-based carbon nucleophiles in air and their use in organic synthesis.

Since the discovery of Grignard reagents in 1900, the nucleophilic addition of magnesium-based carbon nucleophiles to various electrophiles has become one of the most powerful, versatile, and well-established methods for the formation of carbon-carbon bonds in organic synthesis. Grignard reagents are typically prepared via reactions between organic halides and magnesium metal in a solvent. However, this method usually requires the use of dry organic solvents, long reaction times, strict control of the reaction temperature, and inert-gas-line techniques. Despite the utility of Grignard reagents, these requirements still represent major drawbacks from both an environmental and an economic perspective, and often cause reproducibility problems. Here, we report the general mechanochemical synthesis of magnesium-based carbon nucleophiles (Grignard reagents in paste form) in air using a ball milling technique. These nucleophiles can be used directly for one-pot nucleophilic addition reactions with various electrophiles and nickel-catalyzed cross-coupling reactions under solvent-free conditions.

Solid-state Suzuki-Miyaura cross-coupling reactions: olefin-accelerated C-C coupling using mechanochemistry.

The Suzuki-Miyaura cross-coupling reaction is one of the most reliable methods for the construction of carbon-carbon bonds in solution. However, examples for the corresponding solid-state cross-coupling reactions remain scarce. Herein, we report the first broadly applicable mechanochemical protocol for a solid-state palladium-catalyzed organoboron cross-coupling reaction using an olefin additive. Compared to previous studies, the newly developed protocol shows a substantially broadened substrate scope. Our mechanistic data suggest that olefin additives might act as dispersants for the palladium-based catalyst to suppress higher aggregation of the nanoparticles, and also as stabilizer for the active monomeric Pd(0) species, thus facilitating these challenging solid-state C-C bond forming cross-coupling reactions.

Olefin-accelerated solid-state C-N cross-coupling reactions using mechanochemistry.

Palladium-catalyzed cross-coupling reactions are one of the most powerful and versatile methods to synthesize a wide range of complex functionalized molecules. However, the development of solid-state cross-coupling reactions remains extremely limited. Here, we report a rational strategy that provides a general entry to palladium-catalyzed Buchwald-Hartwig cross-coupling reactions in the solid state. The key finding of this study is that olefin additives can act as efficient molecular dispersants for the palladium-based catalyst in solid-state media to facilitate the challenging solid-state cross-coupling. Beyond the immediate utility of this protocol, our strategy could inspire the development of industrially attractive solvent-free palladium-catalyzed cross-coupling processes for other valuable synthetic targets.