CYRENE™: A New Bio-based Dipolar Aprotic Solvent

[ACSGCI]

Contributed by Jane Murray, Ph.D., Global Head of Green Chemistry, Merck KGaA, Darmstadt, Germany (MilliporeSigma)

Summary

Increasing the availability of safer, sustainable solvents is expected to significantly impact industrial Green Chemistry programs. Cyrene™ [(-)-Dihydrolevoglucosenone] is a safer, bio-based alternative to petroleum-derived DMF (Dimethylformamide) and NMP (N-Methyl-2-pyrrolidone)¹. Despite only recently becoming available in the quantities required for solvent usage, Cyrene™ has been successfully employed as a greener substitute in a number of industrially relevant applications, including graphene synthesis² and carbon cross-coupling reactions^3,4.

Introduction

Fossil-derived solvents often constitute the bulk of a reaction or formulation; sustainable and safer alternatives are sought in order to address environmental, health and safety concerns, in addition to increasing regulatory restrictions. Recent attention has focussed on finding alternatives to dipolar aprotic solvents, DMF and NMP, due to increasing regulatory limitations resulting from their associated reproductive toxicity. Both the aforementioned solvents were recently added to the European Chemical Agency’s (ECHA) candidate list of Substances of Very High Concern (SVHC) for Authorisation.                       

Cyrene™ was developed by Circa Group in partnership with Professor James Clark, Ph.D., at the University of York’s Green Chemistry Centre of Excellence (GCCE)¹. Its multifunctional fused ring structure affords a polarity similar to NMP without the inclusion of the amide functionality that is associated with the reproductive toxicity of NMP and DMF.  It is produced in only two steps from non-food cellulose, via a manufacturing process that is almost energy neutral and releases water to the environment. Cyrene™ has a density of 1.25g/mL and does not contain any chlorine, sulfur or nitrogen heteroatoms, which can present end-of-life pollution issues and create corrosive by-products if incinerated. It also has very low acute (LD50) and aquatic (EC50) toxicities that are well above the hazard thresholds defined by the Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Additionally, Cyrene™ is biodegradable and safer to handle than many oxygenated solvents due to its flash point of 108°C. It is stable to oxidation and (at end-of-life) upon incineration or biodegradation yields only carbon dioxide and water.

Material Science Applications 

Graphene is a disruptive technology with potential applications spanning sustainable energy, biomedical, apparel and electronics. Despite its promise, commercialization is currently limited due to the challenges of manufacturing at scale. The common production method utilizing liquid exfoliation of graphite often results in low concentrations and employs NMP. Clark et al found that Graphene dispersions, obtained when NMP was substituted with Cyrene™, were an order of magnitude more concentrated2. The superior performance was attributed to the green solvent’s optimum polarity and high viscosity resulting in the creation of larger and less defective graphene flakes. This is anticipated to support graphene production at scale and contribute towards this revolutionary material realizing its commercial potential.

Interestingly, Katz et al. demonstrated that Cyrene™ could also be successfully employed as an alternative to DMF in the synthesis of metal-organic frameworks⁵.

Medicinal Chemistry Applications

Cross-coupling reactions are amongst the most utilized in the Pharmaceutical and Agrochemical industries, yet often employ DMF as their reaction medium. Switching to alternative solvents may necessitate increased reaction times, higher temperatures or the introduction of non-commercial catalysts. In partnership with Allan Watson, Ph.D., from the University of St Andrews, we developed a mild and robust method for the Sonogashira reaction employing Cyrene™ (Scheme 1)³. The greener alternative also enabled the cascade synthesis of functionalized indoles and benzofurans via a Cacchi-type annulation. The limitations of employing Cyrene™ as a solvent were also investigated. It was found that organic bases, including NEt₃ and DIPEA, were tolerated at 50 C; however, the inorganic bases tested, with the exception of KOAc, were found to react with the solvent.

     Scheme 1

A mild method was also developed for the Suzuki-Miyaura coupling reaction, employing Cyrene™ as a direct alternative to conventional solvents (DMF, THF and 1,4-dioxane) (Scheme 2)⁴. Excellent generality and functional group tolerance with high yields were obtained on both small and larger scale synthesis.

     Scheme 2

Camp et al. employed Cyrene™ to develop a highly efficient, waste-minimizing method for the synthesis of ureas from isocyanates and secondary amines (Scheme 3)⁶. Notably, their method established a simple work-up procedure: The addition of water to the reaction solution resulted in precipitation of the desired urea. Filtration and washing with water yielded an analytically pure product. Their protocol led to a 28-fold increase in molar efficiency versus industrial standard protocols.

     Scheme 3

Researchers continue to discover new applications for this greener solvent alternative. Cyrene™ was recently awarded Bio-based World News’ European Bio-based Innovation Award—a success that was attributed to it demonstrating that safer greener alternatives may also offer superior performance.

Cyrene™ is commercially available from Merck KGaA, Darmstadt, Germany (MilliporeSigma).

References

1. Sherwood, J.; De bruyn, M; Constantinou, A.; Moity, L.; McElroy, C. R; Farmer, T. J; Duncan, T.; Raverty, W.; Hunt, A. J.; Clark, J. H. Chem Commun., 2014, 50, 9650 DOI: 10.1039/c4cc04133j
2. Salavagione, H. J.;  Sherwood, J.;  De Bruyn, M.; Budarin, V. L.; Ellis, G. J.; Clark, J. H.; Shuttleworth, P. S. Green Chem. 2017, 19, 2550-2560 DOI: 10.1039/C7GC00112F
3. Wilson, K. L.; Kennedy A. R.; Murray J.; Greatrex, B.; Jamieson, C.; Watson, A. J. B.; Beilstein J. Org. Chem. 2016, 12, 2005–2011 DOI:10.3762/bjoc.12.187
4. Wilson, K. L;  Murray, J.; Jamieson, C.; Watson, A. Synlett, 2017, 28, A-E DOI: 10.1055/s-0036-1589143
5. Zhang, J.; White, G.; Ryan, M.; Hunt, A. J.; Katz, M. ACS Sustainable Chem. Eng., 2016, 2, 7186-7192  DOI: 10.1021/acssuschemeng.6b02115
6. Mistry, L.; Mapesa, K.; Bousfield, T. W.; Camp, J. E. Green Chem., 2017, 19, 2123 DOI: 10.1039/C7GC00908A

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