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(121a) Synthesis of Paracetamol and 4-Aminophenol from Lignin-Derived Hydroquinone

Park, J. - Presenter, Columbia University
Bommarius, A., Georgia Institute of Technology
Sievers, C., Georgia Institute of Technology
Hatzell, M., Georgia Institute of Technology
The active pharmaceutical ingredient (API) paracetamol, contained in over-the-counter (OTC) drugs such as Tylenol®, is one of the most widely used pharmaceuticals worldwide. Supply chain shortages due to COVID-19 have demonstrated the reliance of many nations on imports for their paracetamol supplies. These factors have raised interest in developing new methods of synthesizing paracetamol.

An important bottleneck to the synthesis of paracetamol is access to 4-aminophenol as an intermediate. While the acetylation of 4-aminophenol to paracetamol is selective and fast, acquiring 4-aminophenol is a significant challenge. The traditional synthesis of 4-aminophenol through the nitration of benzene is environmentally unfriendly because of factors such as high acid/salt waste and a reliance on petrochemicals for the feedstock. Lignocellulosic biomass offers an attractive route to paracetamol. Hydroquinone is a promising starting point for the synthesis of 4-aminophenol because it can be accessed through phenol, a significant product of lignin depolymerization. Aminating hydroquinone to form 4-aminophenol is a promising route that may improve Green Chemistry metrics for synthesizing this important intermediate.

A key difficulty to the synthesis of 4-aminophenol from hydroquinone is deciding the optimal route. We have examined the performance of several amination agents such as ammonium hydroxide, hydrazine monohydrate, ammonium chloride, and ammonium acetate regarding the direct amination of hydroquinone, targeting values such as conversion, yield, and selectivity. Choosing an ideal amination agent is not straightforward, as the amination step is rather slow and unselective, requiring high temperatures and long reaction times. A preliminary reaction mechanism suggests the importance of protonating hydroquinone to form a good leaving group for nucleophilic attack by the aminating agent. As such, we have examined the effect of various acidic catalysts such as zeolites, metal phosphates, metal oxides, and heteropoly acids, as well as the effect of pH, on the reaction conditions. A secondary issue is the stability of 4-aminophenol: under the reaction conditions, 4-aminophenol is prone to further reaction, acting as an additional nucleophile and forming high molecular weight compounds as side products. For that reason, we will also discuss the viability of a one pot synthesis, in which amination and acetylation are done simultaneously, with the acetylating agent “shielding” 4-aminophenol from further reaction to various side products.