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Green Chemistry

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":

  1. Waste prevention instead of remediation
  2. Atom economy or efficiency
  3. Use of less hazardous and toxic chemicals
  4. Safer products by design
  5. Innocuous solvents and auxiliaries
  6. Energy efficiency by design
  7. Preferred use of renewable raw materials
  8. Shorter syntheses (avoid derivatization)
  9. Catalytic rather than stoichiometric reagents
  10. Design products to undergo degradation in the environment
  11. Analytical methodologies for pollution prevention
  12. 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:


Woodward Reaction

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.


Upjohn Dihydroxylation

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

Green Chemistry Conferences
Introduction to the Concept of Green Chemistry
More Links on Green Chemistry


Books on Green Chemistry


Green Chemistry and Catalysis

Roger A. Sheldon, Isabel Arends, Ulf Hanefeld
Hardcover, 434 Pages
First Edition, 2007
ISBN-13: 978-3-527-30715-9
Wiley-VCH


Chemistry in Alternative Reaction Media

D. J. Adams, P. J. Dyson, S. J. Taverner
Paperback, 268 Pages
First Edition, November 2003
ISBN: 0-471-49849-1
Wiley


Recent Literature

Display all abstracts


An "on-water" reaction of (thio)isocyanates with amines enables a facile, sustainable, and chemoselective synthesis of unsymmetrical (thio)ureas. The physical nature and solubility of reagents in water are responsible for the observed reaction rate and selectivity. The process offers simple product isolation through filtration and the recycling of the water effluent and avoids the use of toxic VOCs.
A. D. Karche, P. Kamalakannan, R. Powar, G. G. Shenoy, K. J. Padiya, Org. Process Res. Dev.., 2022, 26, 3141-3152.


Iron(II) phthalocyanine catalyzes a photo-thermo-mechanochemical synthesis of quinolines. This solvent-free transformation features a cost-efficient catalytic system and operational simplicity, and shows good substrate tolerance, providing a green alternative to existing thermal approaches.
L. Liu, J. Lin, M. Pang, H. Jin, X. Yu, S. Wang, Org. Lett., 2022, 24, 1146-1151.


A scalable cyanation of gem-difluoroalkenes to (hetero)arylacetonitrile derivatives offers mild reaction conditions, excellent yields, wide substrate scope, and broad functional group tolerance. Significantly, the use of aqueous ammonia entirely avoids toxic cyanating reagents or metal catalysis and enables a green synthesis of arylacetonitriles.
J.-Q. Zhang, J. Liu, D. Hu, J. Song, G. Zhu, H. Ren, Org. Lett., 2022, 24, 786-790.


A mild nickel-catalyzed reductive cross-coupling between (hetero)aryl bromides and vinyl acetate provides a variety of vinyl arenes, heteroarenes, and benzoheterocycles. Importantly, dimethyl isosorbide as solvent makes this protocol more sustainable.
M. Su, X. Huang, C. Lei, J. Jin, Org. Lett., 2022, 24, 354-358.


An environment-friendly and economic CuCl2-catalyzed C-S bond-formation enables the synthesis of diaryl chalcogenides in very good yields from iodobenzenes and benzenethiols/1,2-diphenyldisulfanes in the presence of N,N'-dimethylethane-1,2-diamine (DMEDA) as ligand, base, and solvent. The catalytic system (CuCl2/DMEDA) is inexpensive, conveniently separable, and recyclable.
G. Shen, Q. Lu, Z. Wang, W. Sun, Y. Zhang, X. Huang, M. Sun, Z. Wang, Synthesis, 2022, 54, 184-198.


(E)-β-Iodo vinylsulfones are synthesized in very good yields under ultrasound irradiation using alkynes, sulfonyl hydrazides, potassium iodide and hydrogen peroxide. The key features of this protocol are the speed and efficiency of the reactions.
C. Zhou, X. Zeng, Synthesis, 2021, 53, 4614-4620.


An Ir-catalyzed synthesis of functionalized quinolines from 2-aminobenzyl alcohols and α,β-unsaturated ketones tolerates a broad range of functional groups, offers high efficiency, is environmentally benign, and can be performed on a gram scale. Alkali is essential for the high selectivities of this catalytic system.
N. Luo, H. Shui, Y. Zhong, J. Huang, R. Luo, Synthesis, 2021, 53, 4516-4524.


Cyclic ketones were quickly and quantitatively converted to 5-, 6-, and 7-membered lactones by treatment with Oxone, a cheap, stable, and nonpollutant oxidizing reagent in 1 M NaH2PO4/Na2HPO4 water solution (pH 7). These simple and green conditions avoid the formation of hydroxyacid. With some changes, the method can also be applied to water-insoluble ketones.
V. Bertolini, R. Appiani, M. Pallavicini, C. Bolchi, J. Org. Chem., 2021, 86, 15712-15716.


Pd/C can be used as a catalyst for nitro group reductions at very low Pd loading either in the presence of triethylsilane as a transfer hydrogenating agent or simply using a hydrogen balloon. With this technology, a series of nitro compounds was reduced to the desired amines in high yields. Both the catalyst and surfactant were recycled several times without loss of activity.
X. Li, R. R. Thakore, B. S. Takale, F. Gallou, B. H. Lipshutz, Org. Lett., 2021, 23, 8114-8118.


Reductive aminations of shelf-stable bisulfite addition compounds of aldehydes can be run under aqueous micellar catalysis conditions with readily available α-picolineborane as the stoichiometric hydride source. Recycling of the aqueous reaction medium is easily accomplished.
X. Li, K. S. Iyer, R. R. Thakore, D. K. Leahy, J. D. Bailey, B. H. Lipshutz, Org. Lett., 2021, 23, 7205-7208.


A transition-metal-free and scalable C-N coupling protocol achieves the synthesis of 2-aminobenzothiazoles from 2-chlorobenzothiazoles and primary amines under solvent-free conditions. Moreover, introducing an appropriate amount of NaH completely switched the selectivity from mono- toward di-heteroarylation.
H. Cheng, Y.-Q. Zhu, P.-F. Liu, K.-Q. Yang, J. Yan, W. Sang, X.-S. Tang, R. Zhang, C. Chen, J. Org. Chem., 2021, 86, 10288-10302.


A catalyst- and metal-free visible-light-mediated protocol enables the iodoamination of miscellaneous olefins in high yields under environmentally benign reaction conditions using DMC as green and biodegradable solvent. Furthermore, the protocol allows for late-stage functionalization of bioactive molecules and can be scaled to gram quantities of product.
S. Engl, O. Reiser, Org. Lett., 2021, 23, 5581-5586.


The combination of a riboflavin-derived organocatalyst and molecular iodine successfully promoted the aerobic oxidation of thiols to disulfides under metal-free mild conditions at room temperature. The the biomimetic flavin catalyst enables the transfer of electrons from the iodine forming the basis for a green oxidative synthesis of disulfides from thiols.
M. Oka, R. Kozako, H. Iida, Synlett, 2021, 32, 1227-1230.


A copper-catalyzed (Cu(OAc)2ĚH2O/(R)-3,4,5-MeO-MeO-BIPHEP) reduction of aryl/heteroaryl ketones provides nonracemic secondary alcohols in very good yields with excellent ee values in an aqueous micellar medium in the presence of PMHS as inexpensive, innocuous, and convenient stoichiometric hydride source.
D. M. Fialho, E. Etemadi-Davan, O. C. Langner, B. S. Takale, A. Gadakh, G. Sambasivam, B. H. Lipshutz, Org. Lett., 2021, 23, 3283-3286.


Water-soluble amide iridium complexes catalyze transfer hydrogenation reduction of N-sulfonylimines under environmentally friendly conditions, affording a series of sulfonamide compounds in excellent yields. This protocol gives an operationally simple, practical, and environmentally friendly strategy for synthesis of sulfonamide compounds.
H. Wen, N. Luo, Q. Zhu, R. Luo, J. Org. Chem., 2021, 86, 3850-3859.


A sulfination of allenic carbonyl compounds provides a wide variety of vinylic sulfones in good yields in aqueous media under very mild conditions. This atom economic reaction offers wide functional group tolerance and a simple isolation by filtration for some products.
J. Goh, M. Maraswami, T.-P. Loh, Org. Lett., 2021, 23, 1060-1065.


Synthesis of Sulfonamide-Based Ynamides and Ynamines in Water
L. Zhao, H. Yang, R. Li, Y. Tao, X.-F. Guo, E. A. Anderson, A. Whiting, N. Wu, J. Org. Chem., 2021, 86, 1938-1947.


Rhodium complexes with chiral bisphospholanes are highly enantioselective catalysts for the asymmetric hydrogenation of functionalized olefins such as dehydroamino acid derivatives, itaconic acid derivatives, and enamides. The use of the hydroxyl phospholane system enables hydrogenation of some substrates in water with >99% ee and 100% conversion (e.g., itaconic acid).
W. Li, Z. Zhang, D. Xiao, X. Zhang, J. Org. Chem., 2000, 65, 3489-3496.


By using Yb(OTf)3 as a catalyst and under solvent-free reaction conditions, the yields of the one-pot Biginelli reaction can be increased while the reaction time was shortened. In addition, the catalyst can be easily recovered and reused. It not only led to economical automation but also reduces hazardous pollution to achieve environmentally friendly processes.
Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem., 2000, 65, 3864-3868.


Zinc(II) catalyzes a single-step protocol for the Beckmann rearrangement using hydroxylamine-O-sulfonic acid (HOSA) as the nitrogen source in water. This environmentally benign and operationally simple method efficiently produces secondary amides under open atmosphere in a pure form after basic aqueous workup.
S. Verma, P. Kumar, A. K. Khatana, D. Chandra, A. K. Yadav, B. Tiwari, J. L. Jat, Synthesis, 2020, 52, 1841-1846.


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