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 metal-free regio- and stereoselective intermolecular hydroamination of arylacetylenes with aliphatic secondary amines provides various (E)-enamines in the presence of ethylene glycol as a solvent. The solvent plays a major role through hydrogen bonding and proton exchange.
J. Bahri, N. Tanbouza, T. Ollevier, M. Taillefer, F. Monnier, Synthesis, 2019, 51, 2086-2090.
The use of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as catalyst enables a Machetti-De Sarlo reaction of nitroalkenes with alkynes/alkenes under sustainable conditions to afford a library of isoxazole/isoxaline products.
M. Vadivelu, S. Sampath, K. Muthu, K. Karthikeyan, C. Praveen, J. Org. Chem., 2019, 84, 13636-13645.
Hydrogen peroxide as an eco-friendly oxidant provides hydroxylation products of arylboronic acids in an efficient manner under metal- and base-free aerobic in the presence of a room-temperature ionic liquid (RTIL).
E.-J. Shin, G.-T. Kown, S.-H. Kim, Synlett, 2019, 30, 1815-1819.
1,3-Thiazolidine-2-thiones can be prepared from β-amino alcohols and potassium ethylxanthate as the starting materials in the presence of ethanol.
Z. Lu, Y.-Q. Yang, W. Xiong, Synlett, 2019, 30, 713-716.
An aerobic oxidation of a wide range of aldehydes to carboxylic acids in both organic solvent and water under mild conditions is catalyzed by 5 mol % N-hydroxyphthalimide (NHPI) as the organocatalyst in the presence of oxygen as the sole oxidant. No transition metals or hazardous oxidants or cocatalysts were involved.
P.-F. Dai, J.-P. Qu, Y.-B. Kang, Org. Lett., 2019, 21, 1393-1396.
A general, selective, and atom economic metal-catalyzed conversion of primary diols and amines to highly valuable 2,5-unsubstituted pyrroles is catalyzed by a stable manganese complex in the absence of organic solvents. Water and molecular hydrogen are the only side products. The reaction shows unprecedented selectivity, avoiding the formation of pyrrolidines, cyclic imides, and lactones.
J. C. Borghs, Y. Lebedev, M. Rueping, O. El-Sepelgy, Org. Lett., 2019, 21, 70-74.
The use of tribromoisocyanuric acid enables a simple and efficient one-pot protocol for the synthesis of 2-aminothiazoles from readily available β-keto esters via α-monohalogenation in aqueous medium and a subsequent reaction with thiourea and DABCO. Extension of the reaction to thioacetamide and o-phenylenediamine led to 2-methylthiazole and quinoxalines, respectively.
V. S. C. de Andrade, M. C. S. de Mattos, Synthesis, 2018, 50, 4867-4874.
A direct and efficient palladium-catalyzed reductive coupling of nitroarenes with phenols provides various N-cyclohexylaniline derivatives in good yields using safe and inexpensive sodium formate as the hydrogen donor.
K.-J. Liu, X.-L. Zeng, Y. Zhang, Y. Wang, X.-S. Xiao, H. Yue, M. Wang, Z. Tang, W.-M. He, Synthesis, 2018, 50, 4637-4644.
The use of tert-butyl hydroperoxide (TBHP) as a terminal oxidant in the presence of catalytic amount of tetrabutylammonium iodide and imidazole enables a transition-metal-free synthesis of aryl esters in high yield starting from benzylic primary alcohols and aliphatic alcohols. These reactions are highly chemoselective and tolerate a wide range of substituents.
S. Nandy, A. Ghatak, A. K. Das, S. Bhar, Synlett, 2018, 29, 2208-2212.
Selective oxyhalogenations of alkynes were achieved in water under very mild conditions in the presence of inexpensive halogenating reagents, such as N-bromosuccinimide and N-chlorosuccinimde, and FI-750-M as amphiphile. No halogenation at the aromatic rings was detected. Reaction medium and catalyst can be recycled.
L. Finck, J. Brals, B. Pavuluri, F. Gallou, S. Handa, J. Org. Chem., 2018, 83, 7366-7372.
A CuI-based catalytic system in combination with an easily accessible prolinamide ligand enables an Ullmann-type cross coupling of a variety of aromatic, aliphatic amines with aryl halides in aqueous media. The method is mild and tolerates air and a wide range of functional groups. Secondary amines like heteroaromatic amines and nucleobases afford the corresponding coupling products in good to excellent yields too.
G. Chakraborti, S. Paladhi, T. Mandal, J. Dash, J. Org. Chem., 2018, 83, 7347-7359.
I2-mediated oxidative C-N and N-S bond formations in water enable a metal-free, environmentally benign and convenient strategy for the synthesis of 4,5-disubstituted/N-fused 3-amino-1,2,4-triazoles and 3-substituted 5-amino-1,2,4-thiadiazoles from isothiocyanates. The scalable protocols exhibited excellent substrate tolerance.
N. Jatangi, N. Tumula, R. K. Palakodety, M. Nakka, J. Org. Chem., 2018, 83, 5715-5723.
Molecular iodine catalyses a benzylic sp3 C-H bond amination of 2-aminobenzaldehydes and 2-aminobenzophenones with benzylamines to provide quinazolines in very good yields. The use of oxygen as an oxidant combined with the transition-metal-, additive- and solvent-free conditions makes the methodology green and economical. 2-Aminobenzyl alcohols could also used as starting materials.
D. S. Deshmukh, B. M. Bhanage, Synlett, 2018, 29, 979-985.
A bulky monothiourea-Pd complex shows a high activity and recyclability in aerobic aqueous Suzuki-Miyaura reactions of aryl bromides with arylboronic acids. The catalyst can be reused at least five times without any significant loss of catalytic activity. TEM analysis and the catalytic activity of the observed black precipitate reveal that Pd nanoparticles are formed and are stabilized by the carboxylic-functionalized thiourea ligands.
W. Chen, X.-Y. Lu, B.-Hua, W.-g. Yu, Z.-n. Zhou, Y. Hu, Synthesis, 2018, 50, 1499-1510.
A large proportion of Suzuki-Miyaura cross-couplings employ dipolar aprotic solvents; however, current sustainability initiatives and increasingly stringent regulations advocate the use of alternatives that exhibit more desirable properties. The suitability of the bio-derived solvent Cyrene is evaluated as a reaction medium for this benchmark transformation from discovery to gram scale.
K. L. Wilson, J. Murray, C. Jamieson, A. J. B. Watson, Synlett, 2018, 29, 650-654.
Sustainable HandaPhos-ppm Palladium Technology for Copper-Free Sonogashira Couplings in Water under Mild Conditions
S. Handa, J. D. Smith, Y. Zhang, B. S. Takale, F. Gallou, B. H. Lipshutz, Org. Lett., 2018, 20, 542-545.
The use of zirconyl nitrate as a water-tolerant Lewis-acid catalyst enables a simple, green, and efficient intramolecular cyclization of o-aminochalcones to provide 2-aryl-2,3-dihydroquinolin-4(1H)-ones under mild reaction conditions with improved yields.
A. Gorepatil, P. Gorepatil, M. Gaikwad, D. Mhamane, A. Phadkule, V. Ingle, Synlett, 2018, 29, 235-237.
The very inexpensive carbonyl iron powder (CIP), a highly active commercial grade of iron powder, enables an especially mild, safe, efficient, and environmentally responsible reduction of aromatic and heteroaromatic nitro groups in water. These reductions are conducted in a recyclable aqueous reaction medium in the presence of nanomicelles composed of TPGS-750-M.
N. R. Lee, A. A. Bikovtseva, M. Cortes-Clerget, F. Gallou, B. H. Lipshutz, Org. Lett., 2017, 19, 6518-6521.
The choline- and peroxydisulfate-based environmentally benign biodegradable oxidizing task-specific ionic liquid (TSIL) choline peroxydisulfate (ChPS) was synthesized and characterized. This reagent enables a selective oxidation of alcohols to aldehydes/ketones in very good yields and short reaction time under solvent-free mild reaction conditions without overoxidation to acid.
B. L. Gadilohar, H. S. Kumbhar, G. S. Shankarling, Ind. Eng. Chem. Res., 2014, 53, 19010-19018.
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