Introduction
In recent years, the growing focus on green chemistry has shifted the attention of scientists worldwide toward research areas like the development of eco-friendly solvents and reactions that are either water-based or solvent-free. This rising demand for environmentally responsible methods of producing chemicals has driven the advancement of more sustainable processes. One of the primary challenges faced by the chemical industry is the significant waste generated daily, largely due to the use of solvents. Consequently, replacing commonly used but harmful organic solvents with safer, non-toxic alternatives is crucial. For process chemists, the main goal is to modify reaction protocols by eliminating hazardous solvents or reagents, thereby reducing the amount of waste generated.
Cyrene structure
A laboratory experiment was developed to introduce systems thinking and green chemistry concepts through the synthesis of the cathinone antidepressant and smoking cessation aid, bupropion hydrochloride. The traditional synthesis has several issues from a green chemistry perspective: it uses the toxic solvents N-methylpyrrolidinone (NMP) and dichloromethane (DCM) and other hazardous chemicals including bromine and 12 M hydrochloric acid resulting in 138 kg of waste per kg of product. A greener synthesis has been developed with suitable improvements to the traditional procedure. The reprotoxic NMP and potentially carcinogenic DCM solvents have been substituted with the green biobased solvent Cyrene and ethyl acetate, respectively, and bromine has been substituted with N-bromosuccinimide. An alternate extraction method has also been developed using 1 M hydrochloric acid and ethyl acetate rather than 12 M hydrochloric acid and diethyl ether. These changes have also reduced waste by 92 kg kg–1, and the resultant experiment is much safer to perform.
Scheme 1. Bupropion hydrochloride synthesis
Mephedrone Like Synthesis With Cyrene
Here we describe an experiment based on the synthesis of the common cathinone antidepressant and smoking cessation aid bupropion hydrochloride ((±)-2-(t-butyl-amino)-3′-chloropropiophenone). Marketed under the name Wellbutrin, bupropion has been shown to be an effective antidepressant acting as a dopamine-norepinephrine reuptake inhibitor. Sold under the name Zyban, bupropion is also applicable as a smoking cessation aid.
Bupropion hydrochloride is synthesized in a two-step process by brominating m-chloropropiophenone followed by amination with tert-butylamine and precipitating as its hydrochloride salt (as shown in Scheme 1), and it has already been reported as a suitable organic laboratory experiment. However, from a green chemistry perspective, there are several issues with the synthesis of bupropion hydrochloride. The reprotoxic solvent N-methylpyrrolidinone (NMP) is used, which is now restricted by the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation. Dichloromethane (DCM) is also used, despite being a suspected carcinogen. Other hazardous substances are also required, including elemental bromine (fatal if inhaled), 12M hydrochloric acid (corrosive), and diethyl ether (extremely flammable and forms explosive peroxides). The quantity of waste produced by the reaction was determined using the green metric, E-factor, which includes all reaction masses except water to calculate the waste produced and is shown in eq 1. It was found that 138 kg of waste is produced per kg of product following the traditional synthesis route, whereas 25–100 kg kg–1 is typically produced on average in pharmaceutical industry processes
Bupropion hydrochloride is synthesized in a two-step process by brominating m-chloropropiophenone followed by amination with tert-butylamine and precipitating as its hydrochloride salt (as shown in Scheme 1), and it has already been reported as a suitable organic laboratory experiment. However, from a green chemistry perspective, there are several issues with the synthesis of bupropion hydrochloride. The reprotoxic solvent N-methylpyrrolidinone (NMP) is used, which is now restricted by the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation. Dichloromethane (DCM) is also used, despite being a suspected carcinogen. Other hazardous substances are also required, including elemental bromine (fatal if inhaled), 12M hydrochloric acid (corrosive), and diethyl ether (extremely flammable and forms explosive peroxides). The quantity of waste produced by the reaction was determined using the green metric, E-factor, which includes all reaction masses except water to calculate the waste produced and is shown in eq 1. It was found that 138 kg of waste is produced per kg of product following the traditional synthesis route, whereas 25–100 kg kg–1 is typically produced on average in pharmaceutical industry processes
Cyrene synthesis from biomass
Dihydrolevoglucosenone or 6,8-dioxabicyclo[3.2.1] octanone is a cellulose-derived solvent, which can be synthesized in a twostep process from biomass. The first step for its synthesis was reported back in 1973 by Broido and coworkers, who characterized correctly the chemical structure of levoglucosenone (LGO), as a result of cellulose pyrolysis (Scheme 1). Although Cyrene was synthesized before, the first structural characterization of the molecule was incorrect. Since then, a lot of effort has been put in increasing the conversion of cellulose into LGO.
Scheme 2
Various methods have been developed concerning the pyrolysis of cellulose, mostly by investigating a wide range of acids to succeed in obtaining the highest yields. In 2011, the Circa group reported a thermal method which afforded LGO in 40% yield. The Circa group patented a method for the formation of LGO, which involves the catalytic pyrolysis of biomass using phosphoric acid in sulfolane. Having in hand the best results for producing the main precursor of dihydrolevoglucosenone, Circa initiated the industrial production of this promising derivative under the trade name Cyrene, and since then the interest in its use as a bio-based solvent has been gradually increasing.
The second and final step involves the reduction of levoglucosenone, by hydrogenation, to afford Cyrene (Scheme 1).
In this context, various palladium catalysts have been widely employed, such as Pd/Al2O3 or Pd/C; however, rhodium catalysts and zirconia-supported catalysts have been used as well. Moreover, a one-pot synthesis of Cyrene from levoglucosenone was suggested by Wang and coworkers, while in 2018, levoglucosenone was reduced to Cyrene using an alkene reductase.
The second and final step involves the reduction of levoglucosenone, by hydrogenation, to afford Cyrene (Scheme 1).
In this context, various palladium catalysts have been widely employed, such as Pd/Al2O3 or Pd/C; however, rhodium catalysts and zirconia-supported catalysts have been used as well. Moreover, a one-pot synthesis of Cyrene from levoglucosenone was suggested by Wang and coworkers, while in 2018, levoglucosenone was reduced to Cyrene using an alkene reductase.
Properties of Cyrene
Regarding its chemical structure, Cyrene is an optically active ketone composed of two fused rings, which form a cyclic acetal (Scheme 1). The ring fusion results in a double anomeric effect, which stabilizes the existence of the cyclic acetal. In general, acetals are stable towards bases and nucleophiles and Cyrene is very unstable toward strong acids and oxidizing or reducing agents. Cyrene is a colorless viscous liquid with a high boiling point (227 °C), which offers the possibility to mediate reactions taking place in a wide range of temperatures.
Table 1. Physical properties of Cyrene versus other dipolar aprotic solvents
Cyrene’s polarity profile was studied using DFT experiments, complemented by the Kamlet–Abboud–Taft parameters that were also obtained (Table 1). The results showed that Cyrene has a similar π* value to N-methylpyrrolidone (NMP), which verifies its definition as an aprotic solvent. As far as the Hansen solubility parameters (HSP) are concerned, Cyrene presents a similar dispersion term (δD) to DMSO, a polar term (δp) similar to DMAc and hydrogen bonding interactions (δH) similar to NMP. The density of Cyrene is 1.25 g mL−1 at 293 K. Compared to NMP, DMF, DMSO or DMAc which are listed as hazardous (H360) by the Registration, Evaluation, Authorization and Restriction of CHemicals (REACH), Cyrene has no known toxicity issues. Thus, major pharmaceutical companies seek for an alternative reaction medium. Additionally, Cyrene is biodegradable, biorenewable, nonmutagenic and non-reprotoxic (Table 1). Cyrene is also miscible with water, which appears to be a very interesting property, since the high miscibility in water facilitates Cyrene removal from reaction mixtures using liquid–liquid extraction. This feature is extremely important, especially in industrial scale reactions, since Cyrene can be easily removed from the reaction mixture and upon water distillation, it can be easily reused.
Table 2. Physical Characteristics of Cyrene
Reactions Where Cyrene Fails to Become a Suitable Solvent
Interestingly in most literature reports, researchers tend to present their successful results; however, non-successful results have their own merit. For further reference, reactions where Cyrene is not a compatible solvent could be of high interest. Even though Cyrene appears to be an excellent choice of solvent, its reactivity that arises from its structure in some cases narrows down its use. In 2018, Hunt and coworkers reported that Cyrene had a very low performance when employed in biocatalytic esterifications, although it was commented that neither DMF nor NMP were effective. Their incompatibility with this reaction can be attributed to the fact that polar solvents disrupt the water layer around the enzyme, decreasing its activity. In 2017, Szekely and coworkers attempted to use Cyrene as the solvent in a diastereoselective synthesis of 2,4,5-trisubstituted-2-imidazolines from benzaldehyde and ammonia. The results were far from successful, since no product was obtained. The high reactivity of Cyrene when it is employed as the solvent may cause that failure. Under no circumstances should we forget the nature of Cyrene as a compound, which implies that in reactions, such as the Grignard reaction (Scheme 3A) or aldol reaction (Scheme 3B), it could not be used as the solvent, as it would react.
Scheme 3
Conclusions
In conclusion, Cyrene is becoming a more and more popular green, non-mutagenic and non-toxic reaction medium, due to its compatibility as a solvent with plenty of reactions of great significance for the chemical industry. Even though Cyrene might present some difficulties in its use, due to its chemical properties, Cyrene's safe use and easy disposal outweigh many popular organic but toxic solvents. The last decade has created numerous opportunities, where Cyrene was successfully employed as a green and safe alternative to toxic solvents. Indeed, more surveys are coming to light day by day, where Cyrene can be employed in every-day and traditional reactions in organic chemistry like cathinone synthesis, biocatalysis, materials chemistry, graphene and lignin manipulation. Initial studies showed the enormous potential Cyrene has. We believe that further research would solve the existing difficulties and give new data to develop significant applications of this promising solvent. Building on easy removal and recycling, Cyrene can become the future number one choice as a green solvent. The future hopefully will reveal new and powerful transformations and hopefully new reactivities will arise.
Sources
- Andrew, Oliver B., James Sherwood, and Glenn A. Hurst. "A greener synthesis of the antidepressant bupropion hydrochloride." Journal of Chemical Education 99.9 (2022): 3277-3282. https://pubs.acs.org/doi/abs/10.1021/acs.jchemed.2c00581
- Stini, Naya A., Petros L. Gkizis, and Christoforos G. Kokotos. "Cyrene: a bio-based novel and sustainable solvent for organic synthesis." Green Chemistry 24.17 (2022): 6435-6449. https://pubs.rsc.org/en/content/articlehtml/2022/gc/d2gc02332f
- https://www.sigmaaldrich.com/deepwe.../documents/238/211/greener-solvents-br-mk.pdf
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