(699d) One-Pot Mechanochemical Hydrogenation and Acetylation of 4-Nitrophenol to Paracetamol with a Multi-Phase Ball Mill Reactor

Paracetamol is one of the most widely used active pharmaceutical ingredients in the world. Supply shortages due to recent world events such as COVID-19 have demonstrated the reliance of many countries on paracetamol imports, increasing interest in the development of new green paracetamol synthesis routes to facilitate building new production centers.

Current processes to produce paracetamol begin with petrochemical feedstocks. One way to improve the process is to use lignocellulosic material as a source of the required aromatic unit structures. To that end, the hydrogenation of 4-nitrophenol to 4-aminophenol is a possible alternative to traditional synthesis methods because of the potential renewability of 4-nitrophenol (which may be obtained from lignin-derived phenol) as well as the relatively benign reaction conditions.

Mechanochemical hydrogenation is an exciting Green method of conducting this reaction because of its elimination of the need for solvents as well as its ambient reaction conditions. Traditional hydrogenation processes are often operated in batch phase with solvents and high hydrogen pressures. Hydrogenation through ball milling offers superb mixing between the solid, liquid, and gas phases, often with little to no required solvent aids and atmospheric hydrogen pressures, because of the agitation and surface interactions provided by the physical movement in the reactor.

We examine the mechanochemical transfer hydrogenation of 4-nitrophenol to 4-aminophenol under solvent-free and liquid-assisted conditions using various solid/liquid hydrogenating agents. We also explore a ball mill reactor setup allowing for solvent-free or liquid-assisted mechanochemical hydrogenation with hydrogen gas flow under ambient conditions with high yield. Next, we test a novel ball mill reactor setup with a gas bubbler allowing for simultaneous hydrogenation and acetylation with hydrogen gas and acetic anhydride vapor. Finally, we conduct a Green Chemistry analysis of each reaction for a quantitative examination of their viability.