Researchers convert β-Pinene into renewable feedstock for sustainable paracetamol and ibuprofen

By Vijay Kumar MalesuReviewed by Sophia CoveneyJul 19 2023

In a recent study published in ChemSusChem, researchers developed scalable processes to convert β-pinene into 4-isopropenylcyclohexanone (4-IPEC), a feedstock for synthesizing sustainable versions of paracetamol and ibuprofen. 

Background

Global concerns about fossil fuel's environmental impact drive efforts to develop sustainable pathways for converting biorenewable resources into biofuels and biopolymers. Yet, the potential of transforming biomass into chemicals from non-renewable petrochemicals remains largely unexplored. 

Although several processes involving the conversion of lignocellulosic biomass to benzenoid feedstocks have been developed, most of them are resource-intensive, expensive, and low-yielding.

Monoterpenes, such as turpentine and limonene, offer a promising solution as they can be converted into valuable fragrances, flavorings, vitamins, and more. 

Previous research has proposed protocols for producing sustainable aromatic chemicals, providing eco-friendly alternatives for commercial products like painkillers. This not only benefits the environment but also holds economic promise.

About the study

In this study, various experimental techniques were employed to investigate the synthesis and characterization of several organic compounds. The 1H and 13C nuclear magnetic resonance (NMR) spectra were obtained using Bruker Avance spectrometers with different frequencies, and chemical shifts were referenced to the residual solvent peak. 

The spectra showed specific multiplet patterns, such as singlets, doublets, triplets, and multiplets, providing information on the compound structures.

Infrared spectra were recorded using a Perkin Elmer Fourier-Transform Infrared (FT-IR) spectrometer, providing valuable data on functional groups present in the compounds. Mass spectrometry was performed using a Bruker Daltonics micrOTOF electrospray time-of-flight (ESITOF) mass spectrometer, revealing molecular weights and fragmentation patterns. 

Melting points were determined using a Buchi 535 melting point apparatus, and thin-layer chromatography was employed for purification.

The synthesis of nopinone involved ozonolysis of β-pinene followed by the addition of triethylamine. The resulting nopinone was characterized through NMR, yielding a 91% yield. 

Another reaction, the synthesis of 4-(1-hydroxy-1-methylethyl)-cyclohexanone (4-HMEC), was carried out using two different methods, batch and continuous flow protocols, resulting in a yield of 86-89%.

The synthesis of 4-IPEC was achieved by heating 4-HMEC with alumina, resulting in an 80% yield. 4-Acetylcyclohexanone (4-ACH) was obtained by subjecting 4-IPEC to ozonolysis, with a yield of 96%. The synthesis of 4-hydroxyacetophenone (4-HAP) involved hydroxylamine and heating the resulting mixture to yield 92% of the product.

The compounds 4-HAP, 4-IPEC, and 4-ACH were used in the synthesis of (rac)-1-isobutyl-4-(prop-1-en-2-yl)cyclohexan-1-ol (1), (rac)-4-(1-hydroxypropan-2-yl)-1-isobutylcyclohexan-1-ol (2), and (rac)-2-(4-hydroxy-4-isobutylcyclohexyl)propanoic acids 4a/4b, respectively. These acids were then converted to the final compound, (rac)-ibuprofen, using Pd-catalyzed aromatization reactions.

Study results

The researchers aimed to develop a practical and efficient method for producing sustainable versions of commonly used painkillers, such as paracetamol and (rac)-ibuprofen, by utilizing renewable resources. Their starting point was β-pinene, a compound found in abundance in natural sources like turpentine and limonene.

The first step of their synthetic strategy involved converting β-pinene into a key intermediate called 4-IPEC. This transformation required careful orchestration of oxidation, ring-opening, and dehydration reactions. They successfully achieved this goal through a series of chemical reactions, ensuring that the intermediate was obtained with high purity and good yield.

With 4-IPEC in hand, the researchers then focused on converting it into paracetamol. They utilized a technique known as oxidative aromatization, catalyzed by a palladium-based catalyst, to transform 4-IPEC into a compound called 4-ACH.

Further oxidation and rearrangement steps eventually yielded paracetamol, a widely used pain-relieving medication.

In parallel, the researchers also explored synthesizing (rac)-ibuprofen from 4-IPEC. This process involved a different series of chemical reactions, including a Grignard reaction, selective oxidation, and rearrangement steps. These steps successfully led to the formation of (rac)-ibuprofen, another commonly prescribed painkiller.

This synthetic approach uses renewable feedstocks derived from natural sources like turpentine and limonene, making it a more sustainable and environmentally friendly method compared to traditional approaches that rely on non-renewable petrochemicals. 

Furthermore, the researchers demonstrated the scalability of their approach, showing that it could be applied to produce these painkillers cost-effectively on a larger scale. 

Conclusions

In the present study, researchers successfully developed scalable methods to transform β-pinene into sustainable forms of two commonly used painkillers, paracetamol, and (rac)-ibuprofen. They also highlighted the potential of using bioderived 4-HAP as a renewable feedstock for producing aromatic products in a monoterpene biorefinery setting.

Overall, this study is a significant step forward in the quest to develop sustainable pathways for producing essential pharmaceuticals. By utilizing renewable resources and demonstrating the feasibility of large-scale production, the researchers have opened up new possibilities for a greener and more environmentally responsible pharmaceutical industry.

The success of this study is expected to inspire others to design their sustainable routes from renewable resources for essential benzenoid products currently derived from non-sustainable petrochemicals.