Koji Kubota

We have developed the first mechanochemical protocol for a solvent-less palladium-catalyzed conjugate arylation, which was enabled by designing new mechanochemistry-directed bipyridine and chiral pyridine–oxazoline ligands.

An appropriate choice of milling conditions as well as a liquid-assisted grinding additive enable the Amano-PS-IM-catalyzed highly efficient acylative kinetic resolution of secondary alcohols under mechanochemical conditions.

Reactions involving both hydrophobic and hydrophilic molecules present a significant challenge due to the difficulties associated with finding solvents that are capable of effectively accommodating reactants with contrasting solubility properties. Solvent-free conditions offer a potential alternative, albeit that under conventional neat conditions, immiscible reactants often remain poorly mixed at the molecular level, resulting in low reactivity. Here, we demonstrate that mechanochemistry could potentially offer a practical solution to overcome this immiscibility issue. Specifically, we discovered that mechanical agitation by ball milling enables highly efficient Fischer glycosylation reactions of hydrophilic unprotected sugars with a wide range of hydrophobic long-chain aliphatic alcohols, offering straightforward access to various glycolipid derivatives. This type of direct glycosylation has been recognized as a challenging transformation due to the inefficient mixing of the immiscible substrate pairs under conventional conditions. Thus, the present study highlights the promising potential of a mechanochemical approach to tackle longstanding challenges associated with immiscibility in the synthesis of value-added amphipathic small molecules.

Mechanochemical solid‐state organic transformations using ball milling not only represent a sustainable and efficient synthetic approach but also exhibit reactivity patterns that are remarkably different from conventional solution‐phase reactions. However, the rational design of site‐ and chemoselective synthetic strategies that harness the distinct behavior of solid‐state molecules remains largely unexplored. Here, we present a new reaction based on an organic crystal‐engineering approach to achieve monoselective nucleophilic aromatic substitution (S _N Ar) reactions. The mechanochemical solid‐state S _N Ar reactions of perfluoroarene derivatives with carbazoles as nucleophiles selectively afforded the monosubstituted products. In contrast, the corresponding solution‐based reactions yielded a mixture of mono‐ and disubstituted products. Single‐crystal X‐ray diffraction analysis of the monosubstituted products revealed strong π–π interactions between the electron‐deficient perfluoroarene moiety and the electron‐rich carbazole unit. These arene–perfluoarene interactions lead to the formation of crystalline solids that are less reactive than the starting materials, thereby suppressing the second substitution and ensuring pronounced monoselectivity. The present study represents a novel approach that leverages a crystal‐engineering principle to design selective solid‐state organic transformations that are difficult to achieve via conventional solution‐based synthesis.

Mechanochemical solid‐state organic transformations using ball milling not only represent a sustainable and efficient synthetic approach but also exhibit reactivity patterns that are remarkably different from conventional solution‐phase reactions. However, the rational design of site‐ and chemoselective synthetic strategies that harness the distinct behavior of solid‐state molecules remains largely unexplored. Here, we present a new reaction based on an organic crystal‐engineering approach to achieve monoselective nucleophilic aromatic substitution (S _N Ar) reactions. The mechanochemical solid‐state S _N Ar reactions of perfluoroarene derivatives with carbazoles as nucleophiles selectively afforded the monosubstituted products. In contrast, the corresponding solution‐based reactions yielded a mixture of mono‐ and disubstituted products. Single‐crystal X‐ray diffraction analysis of the monosubstituted products revealed strong π–π interactions between the electron‐deficient perfluoroarene moiety and the electron‐rich carbazole unit. These arene–perfluoarene interactions lead to the formation of crystalline solids that are less reactive than the starting materials, thereby suppressing the second substitution and ensuring pronounced monoselectivity. The present study represents a novel approach that leverages a crystal‐engineering principle to design selective solid‐state organic transformations that are difficult to achieve via conventional solution‐based synthesis.

This study demonstrates the facile removal of benzyl-derived protecting groups via ammonia-free, mechanochemically driven Birch reduction using inexpensive and easy-to-handle sodium lumps. Various benzyl-protected alcohols and amines were efficiently deprotected within 30 min. Notably, all synthetic operations can be performed without inert gases or bulk solvents.

Mechanical force has the potential to activate thermodynamically and chemically stable molecules, enabling unique reactions to proceed with lower activation energies compared to those of conventional thermal activation pathways. However, the practical utility of such force-driven transformations in synthetic chemistry remains to be demonstrated. In this study, we developed a mechanochemical strategy for the facile activation of poly(vinyl chloride) (PVC), a stable plastic material, as a convenient and practical hydrochloric acid (HCl)-releasing reagent. Although HCl can be generated from PVC via thermal decomposition processes, elevated temperatures (>250 °C) are required, which restrict their practical applications in chemical synthesis. In contrast, our mechanochemical approach leverages the mechanical energy generated via ball milling to induce the homolytic cleavage of the polymer chains, producing HCl under mild conditions. Preliminary calculations support that our proposed force-induced mechanoradical-related mechanism generates HCl with lower activation energies than thermal activation. Inspired by this finding, we demonstrate the applicability of PVC as a mechanotunable Brønsted-acid-releasing reagent to facilitate direct S_N1-type substitution reactions of allylic and benzylic alcohols with electron-rich (hetero)aromatics, amines, and alcohols as nucleophiles under mild, solvent-free, and moisture-tolerant mechanochemical conditions. Moreover, these reactions proceeded efficiently using PVC-based plastic waste, such as PVC tubing. Beyond the immediate utility of this protocol, this work can be expected to inspire the development of mechanochemical approaches to activate stable, abundant commodity plastic materials for their valorization as chemical reagents in the synthesis of high-value molecules.

Boscalid, the active ingredient in various fungicides used in large quantities worldwide, is traditionally synthesized using solution-based methods that require substantial quantities of reaction solvents and prolonged reaction times, highlighting opportunities for improvement in waste reduction, time efficiency, and energy consumption. Herein, we report a solventless and rapid synthesis of Boscalid via an all-step mechanochemical reaction. This synthetic route comprises three steps: Suzuki–Miyaura cross-coupling, zinc-mediated Béchamp reduction, and amidation with 2-chloronicotinyl chloride. Each mechanochemical reaction proceeded rapidly, and the total reaction time was significantly shorter than that of previous methods. Notably, all synthetic operations can be carried out without an inert gas atmosphere or large amounts of solvent, both of which are required under conventional solution-based conditions. Furthermore, gram-scale synthesis was successfully achieved without any yield loss at each step, highlighting the potential scalability of this protocol.

Mechanochemical organic synthesis using ball milling leverages mechanical energy to drive chemical reactions. Comprehensive understanding of reaction kinetics is vital for the continuous development of mechanochemical synthesis. Unlike conventional solution-based reactions, however, the rate-limiting processes of mechanochemical reactions remain poorly understood due to limited knowledge of molecular dynamics at the interfacial length scales. We have recently developed a scaling theory that considers that the mechanochemical reactions of two solid reactants form a phase rich in products at their interface, where the product-rich phase is assumed to act as a fluid under the influence of a small volume of solvent added to the system. We here extend this theory to predict the rate-limiting process governing mechanochemical reactions. Our theory predicts that the rate-limiting process is determined by both the extent of the dissolution of reactant molecules into the product-rich phase and the flow driven by the applied mechanical stress in this phase. This flow retards or even suppresses the crossover to the diffusion-limited regime by accelerating the diffusion of reactant molecules in the product-rich phase. This new model incorporating both diffusion-limited and reaction-limited kinetics provides a fundamental framework for deeper understanding of mechanochemical organic reactions in ball milling.