A traditional concept in process chemistry has been the optimization of the time-space yield. From our modern perspective, this limited viewpoint must be enlarged, as for example toxic wastes can destroy natural resources and especially the means of livelihood for future generations. In addition, many feedstocks for the production of chemicals are based on petroleum, which is not a renewable resource. The key question to address is: what alternatives can be developed and used? In addition, we must ensure that future generations can also use these new alternatives. "Sustainability" is a concept that is used to distinguish methods and processes that can ensure the long-term productivity of the environment, so that even subsequent generations of humans can live on this planet. Sustainability has environmental, economic, and social dimensions.
Paul Anastas of the U.S. Environmental Protection Agency formulated some simple rules of thumb for how sustainability can be achieved in the production of chemicals - the "Green chemical principles":
- Waste prevention instead of remediation
- Atom economy or efficiency
- Use of less hazardous and toxic chemicals
- Safer products by design
- Innocuous solvents and auxiliaries
- Energy efficiency by design
- Preferred use of renewable raw materials
- Shorter syntheses (avoid derivatization)
- Catalytic rather than stoichiometric reagents
- Design products to undergo degradation in the environment
- Analytical methodologies for pollution prevention
- Inherently safer processes
Implementing these Green Chemical Principles requires a certain investment, since the current, very inexpensive chemical processes must be redesigned. However, in times when certain raw materials become more expensive (for example, as the availability of transition metals becomes limited) and also the costs for energy increase, such an investment should be paid back as the optimized processes become less expensive than the unoptimized ones. The development of greener procedures can therefore be seen as an investment for the future, which also helps to ensure that the production complies with possible upcoming future legal regulations.
A typical chemical process generates products and wastes from raw materials such as substrates, solvents and reagents. If most of the reagents and the solvent can be recycled, the mass flow looks quite different:
Thus, the prevention of waste can be achieved if most of the reagents and the solvent are recyclable. For example, catalysts and reagents such as acids and bases that are bound to a solid phase can be filtered off, and can be regenerated (if needed) and reused in a subsequent run. In the production of chemical products on very large scale, heterogeneous catalysts and reagents can be kept stationary while substrates are continuously added and pass through to yield a product that is continuously removed (for example by distillation).
The mass efficiency of such processes can be judged by the E factor (Environmental factor):
Whereas the ideal E factor of 0 is almost achieved in petroleum refining, the production of bulk and fine chemicals gives E factors of between 1 and 50. Typical E factors for the production of pharmaceuticals lie between 25 and 100. Note that water is not considered in this calculation, because this would lead to very high E factors. However, inorganic and organic wastes that are diluted in the aqueous stream must be included. Sometimes it is easier to calculate the E factor from a different viewpoint, since accounting for the losses and exact waste streams is difficult:
In any event, the E factor and related factors do not account for any type of toxicity of the wastes. Such a correction factor (an “unfriendliness” quotient, Q) would be 1 if the waste has no impact on the environment, less than 1 if the waste can be recycled or used for another product, and greater than 1 if the wastes are toxic and hazardous. Such discussions are at a very preliminary stage, and E factors can be used directly for comparison purposes as this metric has already been widely adopted in the industry.
Another attempt to calculate the efficiency of chemical reactions that is also widely used is that of atom economy or efficiency. Here the value can be calculated from the chemical equation:
Atom efficiency is a highly theoretical value that does not incorporate any solvent, nor the actual chemical yield. An experimental atom efficiency can be calculated by multiplying the chemical yield with the theoretical atom efficiency. Anyway, the discussion remains more qualitative than quantitative, and does not yet quantify the type of toxicity of the products and reagents used. Still, atom economy as a term can readily be used for a direct qualitative description of reactions.
Considering specific reactions, the development of green methods is focused on two main aspects: choice of solvent, and the development of catalyzed reactions. By way of example, the development of catalyzed reactions for dihydroxylations have made possible the replacement of the Woodward Reaction in the manufacture of steroids, in which huge amounts of expensive silver salts were used and produced, and thus had become an economic factor:
The Woodward reaction can be replaced through the use of stoichiometric quantities of OsO4, but osmium tetroxide is both very toxic and very expensive, making its use on a commercial scale prohibitive. Only in its catalytic variant, which employs N-methylmorpholine-N-oxide as the stoichiometric oxidant and catalytic quantities of OsO4, can this be considered a green reaction that can be used on industrial scale.
Some systems have already been reported in which H2O2 is used to reoxidize the N-methylmorpholine, allowing this material also to be used in catalytic amounts. Considering the atom efficiency using H2O2 as the terminal oxidant, H2O as the stoichiometric byproduct is much better than N-methylmorpholine. Notably, catalytic systems are available in which the osmium catalyst is encapsulated in a polyurea matrix or bound to a resin, so that the catalyst can be more easily recovered and reused. An additional advantage of such polymer-bound catalysts is the avoidance of toxic transition metal impurities, for example in pharmaceutical products.
A key point is still the choice of solvent, as this is the main component of a reaction system by volume (approx. 90%). Chlorinated solvents should be avoided, as many of these solvents are toxic and volatile, and are implicated in the destruction of the ozone layer. Alternative solvents include ionic liquids, for example, which are non-volatile and can provide non-aqueous reaction media of varying polarity. Ionic liquids have significant potential, since if systems can be developed in which the products can be removed by extraction or distillation and the catalyst remains in the ionic liquid, theoretically both the solvent and the catalyst can be reused. The solvent of choice for green chemistry is water, which is a non-toxic liquid but with limited chemical compatibility. On the one hand, reactions such as the Diels-Alder Reaction are often even accelerated when run in an aqueous medium, while on the other hand, many reactants and reagents, including most organometallic compounds, are totally incompatible with water. There is thus a great need to develop newer methods and technologies that would make interesting products available through reactions in water or other aqueous media. For a short review of reactions in water, please check: S. Varma, Clean Chemical Synthesis in Water, Org. Chem. Highlights 2007, February 1. Chemical reactions run under neat conditions (no solvent) and in a supercritical CO2 medium can also be considered as green choices. Other possible improvements can be considered, such as for example replacement of benzene by toluene (as a less toxic alternative), or use of solvents that can be rapidly degraded by microorganisms.
It is quite astonishing to consider the progress that has been made in the development of greener alternatives to traditional reactions. Some examples can be seen in the recent literature section at the end of this page, and this resource is continuously being updated. A good introduction to Green Chemistry with a focus on catalyzed reactions is offered in the book edited by Sheldon, Arends and Hanefeld (Green Chemistry and Catalysis, Wiley-VCH Weinheim, 2007, 1-47.), on which this article is partly based.
Links of Interest
Books on Green Chemistry
Green Chemistry and Catalysis
Roger A. Sheldon, Isabel Arends, Ulf Hanefeld
Hardcover, 434 Pages
First Edition, 2007
Chemistry in Alternative Reaction Media
D. J. Adams, P. J. Dyson, S. J. Taverner
Paperback, 268 Pages
First Edition, November 2003
A reaction between N-benzylideneanilines and Danishefsky's diene proceeds smoothly in acidic aqueous medium in the presence of a catalytic amount of copper(II) triflate and sodium dodecyl sulfate to afford the corresponding 1,2-diphenyl-2,3-dihydro-4-pyridones in excellent yields. The aqueous solution containing the catalyst can be recovered and reused without any loss in efficiency.
D. Lanari, O. Piermatti, F. Pizzo, L. Vaccaro, Synthesis, 2012, 2181-2184.
N,N-diarylammonium pyrosulfate efficiently catalyzes the hydrolysis of esters under organic solvent-free conditions. This reverse micelle-type method is successfully applied to the hydrolysis of various esters without the decomposition of base-sensitive moieties and without any loss of optical purity for α-heterosubstituted carboxylic acids.
Y. Koshikari, A. Sakakura, K. Ishihara, Org. Lett., 2012, 14, 3194-3197.
Self-assembly of copper sulfate and a poly(imidazole-acrylamide) amphiphile provides a highly active, reusable, globular, solid-phase catalyst for click chemistry. The insoluble amphiphilic polymeric imidazole Cu catalyst drove the cycloaddition of various of alkynes and organic azides at very low catalyst loadings and can be readily reused without loss of activity to give the corresponding triazoles quantitatively.
Y. M. A. Yamada, S. M. Sarkar, Y. Uozumi, J. Am. Chem. Soc., 2012, 134, 9285-9286.
An efficient microwave-assisted metal-free amino benzannulation of aryl(4-aryl-1-(prop-2-ynyl)-1H-imidazol-2-yl)methanone with dialkylamines affords various 2,8-diaryl-6-aminoimidazo[1,2-a]pyridines in good yield.
M. Nagaraj, M. Boominathan, S. Muthusubramanian, N. Bhuvanesh, Synlett, 2012, 1353-1357.
A one pot reaction of carbonylimidazolide in water with a nucleophile provides an efficient and general method for the preparation of urea, carbamates and thiocarbamates without an inert atmosphere. Products precipitate out from the reaction mixture and can be obtained in high purity by filtration.
K. J. Padiya, S. Gavade, B. Kardile, M. Tiwari, S. Bajare, M. Mane, V. Gaware, S. Varghese, D. Harel, S. Kurhade, Org. Lett., 2012, 14, 2814-2817.
With a mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO4 with glucose, an efficient and eco-friendly multicomponent cascade reaction of A3-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded therapeutically important versatile N-fused imidazoles.
S. K. Guchhait, A. L. Chandgude, G. Priyadarshani, J. Org. Chem., 2012, 77, 4438-4444.
1,4-Disubstituted-1,2,3-triazoles were obtained in very good yields from azides and terminal alkynes in water in the presence of catalytic amount of β-cyclodextrin as a phase transfer catalyst. Also, one-pot reactions of alkyl bromides, sodium azide, and terminal alkynes were carried out successfully to give 1,4-disubstituted-1,2,3-triazoles.
J.-A. Shin, Y.-G. Lim, K.-H. Lee, J. Org. Chem., 2012, 77, 4117-4122.
The presence of a catalytic amount of copper(II) and an amine base enables a mild method for the installation of the dimethylphenylsilyl group on the β-carbon of electron-deficient olefins at rt. The transformation proceeds efficiently in water within 1.5–5 h to afford β-silylated products in good yields.
J. A. Calderone, W. L. Santos, Org. Lett., 2012, 14, 2090-2093.
Using bis(pinacolato)diboron, catalytic amounts of CuII, and various amine bases in water under atmospheric conditions at rt, acyclic and cyclic α,β-unsaturated ketones and esters are β-borylated in good yield. Mechanistic investigations suggest that the role of the amine is not only to coordinate to CuII but also to activate a nucleophilic water molecule to form a reactive sp2-sp3 diboron complex.
S. B. Thorpe, J. A. Calderone, W. L. Santos, Org. Lett., 2012, 14, 1918-1921.
An efficient CuSO4-catalyzed S-arylation of thiols with aryl and heteroaryl boronic acids at room temperature is established. A wide variety of thiols and arylboronic acids can be converted in the presence of CuSO4 as the catalyst, inexpensive 1,10-phen·H2O as the ligand, oxygen as oxidant, and EtOH as environment-friendly solvent.
H.-J. Xu, Y.-Q. Zhao, T. Feng, Y.-S. Feng, J. Org. Chem., 2012, 77, 2649-2658.
A simple chiral primary amine catalyses a highly efficient reaction for the synthesis of both Wieland-Miescher ketone and Hajos-Parrish ketone as well as their analogues in high enantioselectivity and excellent yields. This procedure represents one of the most efficient methods for the synthesis of these versatile chiral building blocks even in gram scale with 1 mol% catalyst loading.
P. Zhou, L. Zhang, S. Luo, J.-P. Cheng, J. Org. Chem., 2012, 77, 2526-2530.
The of silica-coated magnetic nanoparticles allowed the construction of magnetically recoverable organic hydride compounds. Magnetic nanoparticle-supported BNAH (1-benzyl-1,4-dihydronicotinamide) showed efficient activity in the catalytic reduction of α,β-epoxy ketones. After reaction, the catalyst can be separated by simple magnetic separation and can be reused.
H.-J. Xu, X. Wan, Y.-Y. Shen, S. Xu, Y.-S. Feng, Org. Lett., 2012, 14, 1210-1213.
Activation of diphenylsilane in the presence of a catalytic amount of an N-heterocyclic carbene (NHC) enables hydrosilylation of carbonyl derivatives under mild conditions. Presumably, a hypervalent silicon intermediate featuring strong Lewis acid character allows dual activation of both the carbonyl moiety and the hydride at the silicon center. Some interesting selectivities have been encountered.
Q. Zhao, D. P. Curran, M. Malacria, L. Fensterbank, J.-P. Goddard, E. Lacôte, Synlett, 2012, 433-437.
A water-soluble Cp*Ir complex bearing a bipyridine-based functional ligand can be used as catalyst for a dehydrogenative oxidation of various primary and secondary alcohols to aldehydes and ketones, respectively without any oxidant. The catalyst can be reused.
R. Kawahara, K.-i. Fujita, R. Yamaguchi, J. Am. Chem. Soc., 2012, 134, 3643-3646.
A clean and efficient and metal-free diacetoxylation reaction of alkenes using commercially available peroxyacids as the oxidants is catalyzed by triflic acid. This method enables also oxidative lactonizations of unsaturated carboxylic acids in good to high yields.
Y.-B. Kang, L. H. Gade, J. Org. Chem., 2012, 77, 1610-1615.
A straightforward and efficient method for the synthesis of quinolines via Friedländer reaction of 2-aminobenzaldehyde with various ketones or malononitrile can be conducted in water without using any catalyst at 70˚C.
Q. Shen, L. Wang, J. Yu, M. Liu, J. Qiu, L. Fang, F. Guo, J. Tang, Synthesis, 2012, 389-392.
Aliphatic and/or aromatic esters were converted into the corresponding amides under mild conditions in good to excellent yields in the presence of tert-butoxide, water and air. The reaction is highly efficient, rapid, versatile, green and economical, and could find great practical application in organic synthesis, biochemistry, and industrial chemistry.
B. R. Kim, H.-G. Lee, S.-B. Kang, G. H. Sung, J.-J. Kim, J. K. Park, S.-G. Lee, Y.-J. Yoon, Synthesis, 2012, 42-50.
A sustainable procedure for the Heck-Matsuda reaction between arenediazonium salts and olefins combines the high reactivity attained in homogeneous catalysis with the recovery of palladium metal by simple filtration usually encountered in heterogeneous catalysis by using Pd(OAc)2 in the presence of charcoal.
C. Rossy, E. Fouquet, F.-X. Felpin, Synthesis, 2012, 37-41.
NaI-catalyzed direct condensation of sulfonamides and formamides enables N-sulfonyl formamidine synthesis without hazardous reagents or transition-metal catalysts. The green methodology features high atom economy, operational simplicity, and good tolerance with diverse functional groups.
S. Chen, Y. Xu, X. Wan, Org. Lett., 2011, 13, 6152-6155.
Polyethylene glycol (PEG) is an inexpensive nontoxic and effective medium for the one-pot synthesis of N-substituted azepines under catalyst-free conditions in excellent yields. Environmental acceptability, low cost, high yields, and recyclability of the PEG are the important features of this protocol.
R. Mallepalli, L. Yeramanchi, R. Bantu, L. Nagarpu, Synlett, 2011, 2730-2732.
A facile metal-free oxidative amination of benzoxazole by activation of C-H bonds with secondary or primary amines in the presence of catalytic iodine in aqueous tert-butyl hydroperoxide proceeds smoothly at ambient temperature under neat reaction condition to furnish products in high yields. This user-friendly method produces only tertiary butanol and water as byproducts.
M. Lamani, K. R. Prabhu, J. Org. Chem., 2011, 76, 7938-7944.
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