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

Continuous flow synthesis of antimalarials: opportunities for distributed autonomous chemical manufacturing

The concept of distributed manufacturing of chemicals is presented and discussed, with specific focus on the context of preparing molecules that can combat the development of geographically-localised resistant strains of infectious pathogens. Specifically we present the case of antimalarial compounds and demonstrate that the flow chemistry community have already designed both a machine capable of distrubuted chemical manufacturing and a module that would be capable of producing artemisin derivatives at the point of use

Mechanochemical electrophilic fluorination of liquid beta-ketoesters

An improved substrate scope for the mechanochemical electrophilic fluorination of dicarbonyls is reported. The applicable substrates have now been broadened to include liquid β-ketoesters. Key to this capability is the inclusion of a grinding auxiliary (NaCl) to improve mass transfer and prevent pasting or gumming of the reaction mixture. Notably, the use of a small amount of acetonitrile is critical to increasing the rate of reaction, ensuring complete consumption of starting materials during the short reaction times as well as improving the selectivity for the monofluorinated product in the mill

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

Preparation of difluoromethylthioethers through difluoromethylation of disulfides using TMS-CF2H

We report an operationally simple, metal-free approach for the late-stage introduction of the important lipophilic hydrogen-bond donor motif, SCF2H. This reaction converts diaryl- and dialkyl-disulfides into the corresponding aryl/alkyl–SCF2H through the nucleophilic transfer of a difluoromethyl group with good functional group tolerance. This method is notable for its use of commercially available TMSCF2H, and does not rely on the need for handling of sensitive metal complexes

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

Substrate-dependent activation of the Vibrio cholerae vexAB RND efflux system requires vexR

Vibrio cholerae encodes six resistance-nodulation-division (RND) efflux systems which function in antimicrobial resistance, virulence factor production, and intestinal colonization. Among the six RND efflux systems, VexAB exhibited broad substrate specificity and played a predominant role in intrinsic antimicrobial resistance. The VexAB system was encoded in an apparent three gene operon that included vexR; which encodes an uncharacterized TetR family regulator. In this work we examined the role of vexR in vexRAB expression. We found that VexR bound to the vexRAB promoter and vexR deletion resulted in decreased vexRAB expression and increased susceptibility to VexAB antimicrobial substrates. Sub-strate-dependent induction of vexRAB was dependent on vexR and episomal vexR expression provided a growth advantage in the presence of the VexAB substrate deoxycholate. The expression of vexRAB increased, in a vexR-dependent manner, in response to the loss of RND efflux activity. This suggested that VexAB may function to export intracellular metabolites. Support for this hypothesis was provided by data showing that vexRAB was upregulated in several metabolic mutants including tryptophan biosynthetic mutants that were predicted to accumulate indole. In addition, vexRAB was found to be upregulated in response to exogenous indole and to contribute to indole resistance. The collective results indicate that vexR is required for vexRAB expression in response to VexAB substrates and that the VexAB RND efflux system modulates the intracellular levels of metabolites that could otherwise accumulate to toxic levels

Translating solid state organic synthesis from a mixer mill to a continuous twin screw extruder

A study on the translation of a solid-state synthetic reaction from a mechanochemical mixer-mill to a continuous twin-screw extruder is discussed herein. The study highlights some considerations to be made and parameters to be tested in the context of a model fluorination reaction, which is the first organic fluorination to be attempted using extrusion. Upon optimization, which features the first use of grinding auxiliary solids to enable effective synthetic extrusion, the difluorination reaction was successfully translated to the extruder, leading to a 100-fold improvement in Space Time Yield (STY); 29 kg m−3 day−1 in a mixer mill to 3395 kg m−3 day−1 in a twin screw extruder

Controlling reactivity through liquid assisted grinding: the curious case of mechanochemical fluorination

We have identified an example of a mechanochemically milled organic reaction where liquid-assisted grinding controls the selectivity, such a phenomenon has not been reported/observed before. It was found that upon milling dibenzoylmethane with Selectfluor in the absence of any solvent, a 3 : 1 ratio of monofluorinated : difluorinated product was observed. Whereas, addition of 0.125 mL of acetonitrile (∼10% of the total volume of materials present) to the ground reaction mixture afforded 50 : 1 selectivity. Furthermore, this phenomenon is applicable to a small range of diketone substrates thus far explored. Additionally, we have demonstrated that difluorination can be achieved by simply switching from adding acetonitrile to addition of sodium carbonate. Most notable, in the latter case, is the reduced reaction time compared to a conventional solvent approach, 2 hours in the mill and 24 hours in the flask

A continuous flow-batch hybrid reactor for commodity chemical synthesis enabled by inline NMR and temperature monitoring

Inline, real time NMR and temperature measurements have been used to optimise the continuous flow synthesis of difluoromethyltrimethylsilane (TMSCF2H) by the reduction of the Ruppert-Prakash reagent (TMSCF3). These measurements were used to maximise the space-time-yield, while ensuring this exothermic process remains safe. In this way, a three-fold increase in space-time-yield was achieved compared to the reported batch procedure, isolating 25 g of pure TMSCF2H after 105 min