Mechanochemistry as an emerging tool for molecular synthesis: what can it offer?

Mechanochemistry is becoming more widespread as a technique for molecular synthesis with new mechanochemical reactions being discovered at increasing frequency. Whilst mechanochemical methods are solvent free and can therefore lead to improved sustainability metrics, it is more likely that the significant differences between reaction outcomes, reaction selectivities and reduced reaction times will make it a technique of interest to synthetic chemists. Herein, we provide an overview of mechanochemistry reaction examples, with ‘direct’ comparators to solvent based reactions, which collectively seemingly show that solid state grinding can lead to reduced reaction times, different reaction outcomes in product selectivity and in some instances different reaction products, including products not accessible in solution

Ammonia Synthesis by Mechanochemistry

The design and use of organic, inorganic, and metal-based catalysts is critical to academic and industrial laboratories all around the world. In this framework, ammonia production embodies the most iconic use of catalysis. This review aims to describe the most recent and exciting developments in the mechanocatalytic preparation of ammonia

Mechanochemical Simmons–Smith cyclopropanation via ball-milling-enabled activation of zinc(0)

The bulk solvent-free synthesis of cyclopropanes via a ball-milling-enabled Simmons–Smith reaction is herein described

Evolution of Solid Processing Methods in Continuous Flow Technology: Reactive Extrusion

The frustrations of precipitation, fouling and blockages of liquid-based flow reactors is familiar to all researchers that have worked with continuous flow equipment. There have been many innovative solutions to try and circumvent this issue. This short review will highlight the emerging technique of mechanochemistry and reactive extrusion as a continuous process that can directly work on solid (and liquid) materials and elicit chemical transformations

A multistep continuous flow synthesis machine for the preparation of pyrazoles via a metal-free amine-redox process.

A versatile multistep continuous flow setup is reported for the four-step conversion of anilines into pyrazole products. The synthesis machine incorporates the use of amine-redox chemistry through diazotization and a metal-free vitamin C mediated reduction. The machine can be used for the synthesis of an array of analogues or the scale up of an individual target.We are grateful to the Cambridge Home and European Scholarship Scheme (JSP) and EPSRC (DLB and SVL, grant numbers EP/K0099494/1 and EP/K039520/1) for financial support.This is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C5RE00082

Nickel-Catalyzed Intramolecular Alkene Difunctionalization by Ball-Milling

A mechanochemical nickel-catalyzed intramolecular difunctionalization reaction of alkene tethered aryl halides with alkyl halides is herein described. This method allows for synthesis of 3,3-disubstituted heterocycles, namely oxindoles, with shorter reaction times than solution-phase counterparts. Additionally, this process is solvent minimized, with DMA used in liquid-assisted grinding (LAG) quantities and circumvents the need for chemical activation of the terminal reductant (manganese) through mechanical grinding. The process can be scaled up to yield over a gram of product and modest enantioinduction is possible by utilizing a chiral PyrOx ligand. (Figure presented.)

Mechanochemical activation of zinc and application to Negishi cross-coupling

A form independent activation of zinc, concomitant generation of organozinc species and engagement in a Negishi cross‐coupling reaction via mechanochemical methods is reported. The reported method exhibits a broad substrate scope for both C(sp3)–C(sp2) and C(sp2)–C(sp2) couplings and is tolerant to many important functional groups. The method may offer broad reaching opportunities for the in situ generation organometallic compounds from base metals and their concomitant engagement in synthetic reactions via mechanochemical methods

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

Solventless mechanochemical synthesis represents a technique with improved sustainability metrics compared to solvent-based processes. Herein, we describe a methodical process to run one solventless reaction directly into another through multistep mechanochemistry, effectively amplifying the solvent savings. The approach has to consider the solid form of the materials and compatibility of any auxiliary used. This has culminated in the development of a two-step, one-jar protocol for heterocycle formation and subsequent fluorination that has been successfully applied across a range of substrates, resulting in 12 difluorinated pyrazolones in moderate to excellent yields

Robust Buchwald-Hartwig amination enabled by ball-milling

An operationally simple mechanochemical method for the Pd catalysed Buchwald–Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein

Exploring the generation and use of acylketenes with continuous flow processes

The generation and use of reactive intermediates is well suited to continuous flow processing owing to the ability to scale up reactions, contain hazards and heat solvents past their atmospheric temperature boiling points. Herein we explore the chemistry of acylketenes, generated from commercially available 2,2,6-trimethyl-4H-1,3-dioxin-4-one (TMD, 10) under continuous flow conditions. The developed flow chemistry system is capable of permitting a wide range of applications of these acylketene intermediates, including access to equilibrating processes that result in ketone exchange. Some of the dioxinone products resulting from this study are destabilised towards acylketene generation, this is demonstrated through their ability to generate acylketene at lower reaction temperatures