Going green to keep it safe

We look at how the 12 principles of green chemistry can lower risk to human health in the laboratory Green Chemistry has seen great expansion over the past 20 years with focus being centred on replacing hazardous chemicals with benign alternatives, lowering the risk to the environment and human health. This growth has stemmed from a number of socio-economic factors largely driven by the implementation of legislation and the resulting costs associated with using ‘unclean’ chemical processes; sadly in some cases legislation has been in response to industrial catastrophe (such as the deadly release of methyl isocyanate in Bhopal in 1984¹ and dioxin in Seveso² in 1976). Policies such as REACH³ (Registration Evaluation and Authorisation of Chemicals) and proposed Seveso III⁴, continue to ensure a high level of protection of human health by restricting use of dangerous substances and in some cases, banning them altogether. This has created safe environments and stimulated innovation to identify non-toxic replacements for banned substances. As such, Green Chemistry has evolved to cover an exceptionally wide base from sustainable platform molecules to renewable solvents, clean catalysis and enhanced process efficiency. Regardless of the particular area, all green chemistry practises follow the principle of Green Chemistry designed to reduce risk. Over the page you’ll see key guidelines for researchers, technicians or lab staff wanting to reduce risk in their laboratory. Their relation to the original twelve principles of green chemistry (below) is also indicated. The twelve principles of green chemistry 1) Prevention – It’s better to prevent waste than to treat or clean up waste afterwards. 2) Atom Economy – Design synthetic methods to maximise the incorporation of all materials used in the process into the final product. 3) Less Hazardous Chemical Syntheses – Design synthetic methods to use and generate substances that minimise toxicity to human health and the environment. 4) Designing Safer Chemicals – Design chemical products to affect their desired function while minimising their toxicity. 5) Safer Solvents and Auxiliaries – Minimise the use of auxiliary substances wherever possible make them innocuous when used. 6) Design for Energy Efficiency – Minimise the energy requirements of chemical processes and conduct synthetic methods at ambient temperature and pressure if possible. 7) Use of Renewable Feedstocks – Use renewable raw material or feedstock rather whenever practicable. 8) Reduce Derivatives – Minimise or avoid unnecessary derivatisation if possible, which requires additional reagents and generate waste. 9) Catalysis – Catalytic reagents are superior to stoichiometric reagents. 10) Design for Degradation – Design chemical products so they break down into innocuous products that do not persist in the environment. 11)   Real-time Analysis for Pollution Prevention – Develop analytical methodologies needed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances. 12)   Inherently Safer Chemistry for Accident Prevention – Choose substances and the form of a substance used in a chemical process to minimise the potential for chemical accidents, including releases, explosions, and fires. How to make your lab healthier using Green Chemistry Reagents 1) Avoid use of hazardous reagents – Green Chemistry Principles 3, 4, & 12 Although this sounds very obvious, it is a key factor. Stoichiometric quantities of reactive homogeneous chemicals are frequently used and will always pose a risk, though this can be minimised. Synthetic routes should be periodically reviewed to assess the quantity, reactivity and toxicity of hazardous species as well as the quantity and nature of waste produced, with alternative routes being considered. For instance, dimethyl carbonate can be used with a catalytic quantity of base as a direct replacement of methyl halides, dimethylsulfate or phosgene in methylation and carbonylation reactions⁵. Small quantities of catalytic material are preferred over stoichiometric quantities of activating species, even if yield or efficiency may be slightly lower. This is certainly the case in oxidations and reductions where catalytic reactions are favoured to stoichiometric reagents such as chromates and borohydrides. Often it is possible to convert very reactive or hazardous homogeneous species to heterogeneous materials by immobilising them on supports such as silica or alumina⁶. This has the effect of making them safer and easier to handle, whilst retaining much of the activity. Consult the SIN list⁷ (Substitute It Now) and if one or more of your reagents are listed, try to alter your synthesis to use alternatives. When considering safer chemistry practise, product yield is not always the single most important parameter; especially if the mass balance is made up of unreacted substituents (that can be recycled). 2) Sustainable feedstocks – Green Chemistry Principle 7 The European chemical industry is thought to utilise around 85 million tons equivalent crude oil as non-sustainable feedstock, 70% of which originates from Naptha (constituents of which are known carcinogens) and rest from gas liquids⁸. As such, there is a severe need to source platform chemicals from renewable sources. Several renewable groups have been researched extensively including CO₂ to form alkyl and cyclic carbonates⁹, biomass¹⁰ to extract platform species such as lignin, cellulose, hemicellulose, chitosan, carbohydrates and carboxylic acids (extraction of key chemical species from plants) and waste food¹¹; the first and latter have the added advantage of not competing with the ‘farming for food’ industry. Through mass change from non-sustainable to sustainable chemicals in the laboratory, risk is reduced for anyone involved with the hazardous extraction or purification processes of non-renewables, as well as the resulting pollution and environmental damage caused by these processes. 3) Safer solvents – Green Chemistry Principle 5 The volume of solvent used in a typical reaction or process will almost always outweigh the quantity of reagents and/or catalysts employed, and consequently will contribute significantly towards the waste stream. As such, the solvent toxicity, flammability, difficulty of waste treatment as well as the potential for recycling should be assessed. Though there is no such thing as a universal green solvent, there is significant work published in the field of ‘greener solvents’ and many direct replacements for traditional solvents that have been highlighted. Supercritical CO₂, ionic liquids, water, perfluorinated solvents for biphasic synthesis and biosolvents have a wide range of solvent properties and all exhibit benefits over the petrochemical derived equivalents. Perfluorinated liquids have been at least partly discredited due to environmental concerns and ionic liquids are probably most suitable for niche applications. Bio-based solvents however, seem to have a bright future with major trading regions such as the EU and US strongly encouraging their use. A good example of this is the use of para-cymene, a derivative of limonene extracted from waste citrus peel¹², as a replacement for toluene, (a possible candidate to be a REACH restricted chemical). Cyclic and alkyl carbonates have shown much promise as ‘green’ polar aprotic solvents, with the added attraction that they can be synthesised by utilising waste CO₂¹³. Solvent free syntheses are perhaps the ‘greenest’ reactions of all having a reduced volume of reaction mixture and no solvent waste; this is of course providing the reaction in question is stable, efficient and safe under these conditions. Safer solvents should not just be considered for synthetic chemistry, they apply to analytical chemistry too, for instance, the use of cyclohexane instead of hexane for HPLC analysis, (the latter being a suspected mutagen). See the GSK solvent selection guide for guidance¹⁴. Waste reduction Risk of exposure to hazardous chemicals tends to be greater when handling, storing or treating relatively large quantities of waste generated from a reaction.  As such, minimisation of waste will have a significant impact upon user safety. 4) Only use what you need – Green Chemistry Principle 1 By only using the resources you really need you are immediately reducing wastage, risk and energy required to process the waste. This can be achieved easily by reducing reaction scale and certainly for initial experimental investigation, less is best. 5) Green Metrics – Green Chemistry Principles 2&6 These are fundamental to Green Chemistry practise¹⁵ and allow chemists to assess how efficient a particular reaction or process is. Roger Sheldon’s E-Factor introduced in the late 90s allows calculation of how much waste is produced by a given reaction¹⁶ and enables easy comparisons between different routes to a compound. Other common green metrics include Atom Economy, Effective Mass Yield, Mass Intensity, Carbon Efficiency as well as Life Cycle Assessment; a good overview can be found in Green Chemistry Metrics Measuring and Monitoring Sustainable Processes (Lapkin and Constable)¹⁷. To minimise waste and optimise efficiency and safety, calculate the green chemistry metrics to highlight the weak parts of the synthesis and see if an alternative route is greener. 6) Eliminate use of chemical derivatives, catalysts are key – Green Chemistry Principles 8 & 9 Where possible employ syntheses that avoid the use of protecting or activating groups. Such manipulations add steps to a synthetic route, create waste and are typically indicative of a reaction with poor efficiency. Consider alternative routes that make use of catalysts with high selectivity and aim to balance conversion to product with waste production. 7) Purification and isolation of product – Green Chemistry Principle 1 The quantity of solvent required for flash column chromatography creates very large volumes of solvent waste which is rarely reused, recrystallisation is preferred if possible. Use of solid phase heterogeneous catalysts allows simple filtration to remove the catalyst and the possibility of telescoping reaction steps. Clean Technologies and efficiency The process of thermally heating a reaction mixture in a ‘pot’ is centuries old and highly inefficient. Aside from this, the principle of heating a volume of (often flammable) solvent to reflux poses increased risk, especially when scaled up to an industrial multi-tonne scale. Realisation of these safety implications along with technological development has cause many sectors within the chemical industry to embrace more efficient methods. 8) Continuous flow – Green Chemistry Principle 6 The essential principles of the continuous flow reactor are simple. Pumps are used to mix dissolved reagents and catalyst into a heated coil or into a heated column containing solid phase heterogeneous catalyst. Whilst the reagents reside in the heated coil they react and the product simply elutes out of the reactor. This allows exposure to relatively high concentrations of catalyst, increased conversion and non-stop, continual production of the target molecule. The key benefit of this technology is that only a small proportion of solvent is heated at any one time, with the accumulative quantity of product being comparable or even better than a comparative batch reaction. Process intensification often employs continuous flow (micro reactor) technology and is defined as miniaturisation of a process resulting in a reduction of capital cost, improved inherent safety and energy efficiency¹⁸. Other reduced volume systems such as spinning disc reactors and intensified cross corrugated multifunctional membranes are also used and exhibit enhanced safety due to their low volume characteristic. 9) Microwave reactors – Green Chemistry Principle 6 Though the actual mechanism by which microwave chemistry works has been somewhat of a debate¹⁹, it has proven to be an extremely efficient method of heating reaction mixtures. The equipment is essentially no different to microwave ovens used in the home, albeit a little more powerful. The key safety benefit of this technology is that energy input (and hence heating) to the reaction is started or stopped instantaneously when the power is turned on or off. Conversely, the equivalent thermal heater (stirrer hotplate) will irradiate heat for a significant period of time after the power has been turned off. Further to this, microwave energy can heat a reaction system remotely, in that no surface to surface contact is required and heating rates are often far higher providing the chemical species in question can couple strongly with the microwaves, (dielectric loss and dielectric constant)²⁰. In essence, microwaves offer increased controllability and enhance energy efficiency over chemical reactions, reducing risks associated with heating. References 1) Lepkowski W., Bhopal disaster spotlights chemical hazard issues, Chemical and Engineering News, 1984, 62 (52), p19; Broughton E., The Bhopal disaster and its aftermath: a review, Environmental health a global access science source, 2005, 4 (1), p.6. 2) Margerison T., Wallace M., Hallenstein, D., Seveso – The disaster before the accident, New Scientist, 1981, 89 (1239), p.334. 3) Journal of Exposure Science and Environmental Epidemiology (2007) 17,S1, doi:10.1038/sj.jes.7500618; EXPAND 4) http://www.hse.gov.uk/seveso/introduction.htm. 5) Tundo P., Perosa A., Zecchini F., Methods and Reagents for Green Chemistry, Wiley, 2007, Chapter 4, p.77-78. 6) Clark J. H., Rhodes C. N., Clean Synthesis Using Porous Inorganic Solid Catalysts and Supported Reagents, RSC Clean Technology Monographs, 2000. 7) http://www.chemsec.org/what-we-do/sin-list/sin-database. 8) Tundo P., Perosa A., Zecchini F., Methods and Reagents for Green Chemistry, Wiley, 2007, Chapter 10, p.202-203. 9) North M., Reviews and Accounts ARKIVOC, 2012, (i), p.610. 10) Clark J. H., Deswarte F., Introduction to Chemicals from Biomass, Wiley, 2008. 11) http://www.wastevalor.org/index.html; Clark J. H. et al, Energy & Environmental Science, 2013, 6, p.426. 12) Clark J. H., Macquarrie D. J., Sherwood J., Green Chemistry, 2012, 14, p.90. 13) North M., Chemistry Today, 2012, 30 (3), p.3; North M., Pasquale R., Young C., Green Chemistry, 2010, 12 (9), p.1514; North, M., Pasquale R., Andewandte Chemie Int. Ed., 2009, 48 (16), p.2946. 14) Henderson R. K., Jiménez-González C., Constable D. J. C., Alston S. R., Inglis G. G. A., Fisher G., Sherwood J., Binksa S. P., Curzonsf A. D., Green Chemistry, 2011, 13, p.854; http://www.rsc.org/suppdata/gc/c0/c0gc00918k/c0gc00918k.pdf 15) Constable D. J. C., Curzons A. D., Cunningham V. L., Green Chemistry, 2002, 4, p.521. 16) Sheldon R. A., Chemistry and Industry (London), 1992, p.903; Sheldon R. A., Chemistry and Industry (London), 1997, p.12. 17) Lapkin A., Constable D., Green Chemistry Metrics – Measuring and Monitoring Sustainable Processes, 1^st Ed., Wiley, 2008. 18) Clark J. H., Macquarrie D. J., Handbook of Green Chemistry and Technology, 1^st Ed., Blackwell Science Ltd, 2002, Chapter 15 Process Intensification for Green Chemistry. 19) Rosana M. R., et al, Chemical Science,2012, 3, p.1240; Kappe C. O., et al, Andewandte Chemie Int. Ed., 2012, 52, p.1088; Dudley G. B., Stiegman A. E., Rosana M. R., Andewandte Chemie Int. Ed., 2013, 52 (31) p.7918; Kappe C. O., Andewandte Chemie Int. Ed., 2013, 52 (31), p.7924. 20) Clark J. H., Macquarrie D. J., Handbook of Green Chemistry and Technology, 1^st Ed., Blackwell Science Ltd, 2002, Chapter 17, Applications of Microwaves for Environmentally Benign Organic Chemistry. Authors James Comerford and James Clark of the Green Chemistry Network