We did it again! What? Synthesising compounds thanks to mechanochemistry. This time, we employed resonant acoustic mixing technique (RAM) to study different reactions at multi-gram scale, and we applied green metrics. We demonstrate that this technique can be used to achieve key active pharmaceutical ingredients (APIs), while improving the metrics of traditional-solvent based chemistry. This success has been published in ChemSusChem.
At IMPACTIVE, we use many different mechanochemical processing conditions, such as ball or bead milling, among other, where balls or beads mash the compounds to induce new transformations. RAM, however, is a bit special. This technique usually needs only the help of low-frequency sound waves to enable chemical transformations by intensively mixing the materials under very high acceleration. This means there are no impacts coming from any external milling media. Instead, the reaction-driving forces come from the shearing of particles alone. However, cases in which grinding media were needed to facilitate the reaction were also reported.
RAM is already used in coating technology, alloy materials, or pharmaceutical blending, but it’s a rather novel approach for organic synthesis. Now, we have applied it for the first time for three reactions in organic chemistry! Let’s take a closer look at each of these reactions and the compounds we synthesised!
The Knoevenagel condensation for vanillin barbiturate
The Knoevenagel condensation is a powerful approach to carbon-carbon bond transformations, finding application in polymers, cosmetics, chemical industries, and medicinal chemistry. “We chose it a reference point”, says Christos Chatzigiannis, first author of the paper and IMPACTIVE researcher at the University of Montpellier, in France. It’s also a reaction that has been extensively explored by mechanochemistry, both in batch and in continuous.
Using RAM, we achieved excellent yields with 100% conversion in a very short reaction time, — just 30 minutes, compared to 2.5 hours using traditional solution-based methods. The synthesis of vanillin barbiturate confirmed the potential of RAM in organic synthesis.
The Biginelli multicomponent reaction for the anticancer drug Monastrol
The Biginelli reaction is a three-component reaction. “It’s a very versatile reaction because you can synthesise a wide variety of compounds simply by changing the nature of the starting materials” explains Chatzigiannis. In our study, we used this approach to prepare two target molecules belonging to the dihydro(thio)pyrimidinones family, including Monastrol, endowed with anticancer activity. “The preparation of the model dihydropyrimidinone served as a model compound to optimise the reaction conditions, which we then applied to the biologically active Monastrol,” adds our researcher.
In the dihydropyrimidinones case, the formation of an intermediate phase hampering proper mixing of the reactants initially delivered a moderate yield by RAM. That’s why we introduced some milling balls, to improve mass transport and promote a more efficient mixing. However, in the case of Monastrol, the reaction activated by RAM was much better.
The Biltz synthesis for the antiepileptic drug Phenytoin
The Biltz synthesis is a rearrangement reaction that, in solution, usually requires heating at 90 °C. By RAM, we were able to perform the Biltz synthesis at ambient temperature, achieving one of our best results, yielding nearly quantitative yield, and with excellent green chemistry metrics in comparison with the solution-based process.
“Molecular rearrangements induced by mechanochemistry are still poorly investigated. Herein, RAM was applied for the first time to this class of reactions,” explains Chatzigiannis. And yes, in this case, RAM surpassed expectations.
The final product, Phenytoin, is listed by the World Health Organization as an essential medicine. It’s produced on a large industrial scale each year, so providing a safer and greener synthetic route is of significant value.
Green metrics measurement
In three out of four targets, the yields achieved using RAM were comparable, if not better, to those obtained through traditional solution-based methods. However, what really made the difference was the assessment by green chemistry metrics. In every case, RAM outperformed traditional chemistry.
“The assessment of RAM’s green chemistry metrics has never been done so far, and this is important, as it highlights its potential in terms of sustainability and environmental benefits for organic synthesis conducted by mechanochemistry,” explains Chatzigiannis. “In the end, it’s vital to be able to synthesise these compounds without generating large amounts of waste, avoiding toxic reagents, or hazardous conditions such as high temperatures or flammable solvents.”
We couldn’t forget to mention scalability! While we only went up to a multigram scale, RAM can be an additional approach to go at higher scale.