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
Poly(vinyl chloride)-supported nanoparticles of metallic palladium enable an efficient Suzuki reaction at room temperature. Aryl iodides, bromides, and chlorides underwent smooth reactions in aqueous ethanol under ligand-free conditions to give good yields of the desired biaryl products. The heterogeneous catalyst could be used up to four times with no detectable metal leaching or loss of catalytic efficiency.
M. Samarasimhareddy, G. Prabhu, T. M. Vishwanatha, V. V. Sureshbabu, Synthesis, 2013, 45, 1201-1206.
In the presence of a carbamic acid ammonium salt as an organocatalyst, the Knoevenagel condensation between an active methylene compound and an aromatic aldehyde gave the desired Knoevenagel products in good yields at rt and in a short reaction time under solvent-free conditions. In addition, no extraction, wash, or chromatography steps were needed to obtain a high-purity Knoevenagel product.
N. Mase, T. Horibe, Org. Lett., 2013, 15, 1854-1857.
A catalytic amount of 2-ethynylpyridine promotes the copper(I) chloride catalyzed reaction of azides with alkynes in water at room temperature to afford 1,4-disubstituted 1,2,3-triazoles in good yields. Electron-rich, electron-poor, and sterically crowded substrates can be converted. A study of the additive effect of pyridine derivatives revealed that alkynyl and 2-pyridyl groups were essential for activating the copper catalyst.
H. Hiroki, K. Ogata, S.-i. Fukuzawa, Synlett, 2013, 24, 843-846.
A metal-free and eco-friendly coupling of readily available diaryliodonium salts and arenesulfinates in PEG-400 under microwave irradiation enables the preparation of various diaryl sulfones in high yields and short reaction times under mild conditions. Furthermore, the coupling of diaryliodonium with arenesulfinate salts with and without copper iodide provides a convenient access to various diaryl sulfones with high selectivity.
D. Kumar, V. Arun, M. Pilania, K. P. Chandra Shekar, Synlett, 2013, 24, 831-836.
An aqueous syntheses gives methylimidazo[1,2-a]pyridines, imidazo[1,2-a]pyrazines, and imidazo[2,1-a]isoquinolines without any deliberate addition of catalyst. Using acetonitrile as solvent, Ag-catalyzed intramolecular aminooxygenation produced imidazo[1,2-a]pyridine-3-carbaldehydes in good yields.
D. C. Mohan, S. N. Rao, S. Adimurthy, J. Org. Chem., 2013, 78, 1266-1272.
Mixing an enone, zinc powder, TMEDA, and an alkyl halide in an aqueous micellar environement containing catalytic amounts of Cu(I) and Au(III) enables conjugate additions in water at room temperature via in situ generated organocopper reagents in good yields. In the presence of Ag(I), the amounts of alkyl halide, Zn, and AuCl3 can be reduced dramatically.
B. H. Lipshutz, S. Huang, W. W. Y. Leong, G. Zhong, N. A. Isley, J. Am. Chem. Soc., 2012, 134, 19985-19988.
Solid 1,2-dibromotetrachloroethane (C2Br2Cl4) is a suitable halogenating reagent for the one-pot conversion of sulfones to alkenes by way of the Ramberg-Bäcklund rearrangement. Dibromotetrachloroethane successfully replaces known ozone depleting agents CCl4, CBr2F2 and C2Br2F4. A formal synthesis of E-resveratrol is demonstrated.
S. C. Söderman, A. L. Schwan, J. Org. Chem., 2012, 77, 10978-10984.
An efficient base-catalyzed [3 + 3] oxidative aromatization of α,β-unsaturated carbonyl compounds with dimethyl glutaconate under mild, metal-free conditions affords substituted benzenes in high to excellent yields with oxygen as oxidant and water as sole byproduct. In situ generation of the α,β-unsaturated carbonyl compounds from aldehydes and ketones enables a more convenient tandem [3 + 2 + 1] aerobic oxidative aromatization reaction.
A. Diallo, Y.-L. Zhao, H. Wang, S.-S. Li, C.-Q. Ren, Q. Liu, Org. Lett., 2012, 14, 5776-5779.
Ionic liquids [bmim][X] (X = Cl, Br, I, OAc, SCN) are highly efficient reagents for nucleophilic substitution reactions of sulfonate esters derived from primary and secondary alcohols. The newly developed protocol is very environmentally attractive because the reactions use stoichiometric amounts of ionic liquids as sole reagents without additional solvents and activating reagents. Moreover, these ionic liquids can be readily recycled.
Y. Liu, Y. Xu, S. H. Jung, J. Chae, Synlett, 2012, 23, 2663-2666.
In the presence of oxygen and a small amount of AIBN as radical initiator, primary amines are oxidatively coupled to imines and tertiary amines are cyanated to α-aminonitriles. These metal-free aerobic oxidative coupling reactions may find applications in a wide range of green oxidation chemistry.
L. Liu, Z. Wang, X. Fu, C.-H. Yan, Org. Lett., 2012, 14, 5692-5695.
Utilizing a recyclable tartaric acid-SDS catalyst system help to achieve a green synthesis of 2,3-dihydro/spiroquinazolin-4(1H)-ones via three-component cyclocondensation reaction of isatoic anhydride, amines and aldehydes/ketones. Mechanochemical activation at room temperature lead to significant improvement on previously described methods for the synthesis of such compounds even in large-scale reactions.
R. Sharma, A. K. Pandey, P. M. S. Chauhan, Synlett, 2012, 23, 2209-2214.
N-hydroxyphthalimide (NHPI) catalyzes a metal-free, aerobic oxidative cleavage of olefins. This methodology avoids the use of toxic metals or overstoichiometric amounts of traditional oxidants, showing good economical and environmental advantages. Based on the experimental observations, a plausible mechanism is proposed.
R. Lin, F. Chen, N. Jiao, Org. Lett., 2012, 14, 4158-4161.
An atom-economic, efficient, rapid, and highly regioselective one-pot click reaction allows the synthesis of benzo[e][1,4]oxazepin-5-ones in excellent yields. The method involves epoxide ring-opening-ring-closing cascade with anthranilic acids using neat grinding at room temperature in the presence of lithium bromide as a mild catalyst. Pure products are obtained simply by washing the reaction mixture with warm water.
A. K. Singh, R. Chawla, L. D. S. Yadav, Synthesis, 2012, 44, 2353-2358.
A one-pot conversion of aldehydes to esters interfaces N-heterocyclic carbene-based organocatalysis with electro-organic synthesis to achieve direct oxidation of catalytically generated electroactive intermediates. A broad range of aldehyde and alcohol substrates has been converted. Furthermore, the anodic oxidation reactions are very clean, producing only H2 gas as a result of cathodic reduction.
E. E. Finney, K. A. Ogawa, A. J. Boydston, J. Am. Chem. Soc., 2012, 134, 12374-12377.
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, 44, 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, 23, 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.
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