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":

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:

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

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A simple 2,2'-biphenol-derived phosphoric acid catalyst promotes a dehydrative esterification from an equimolar mixture of carboxylic acids and primary or secondary alcohols in toluene at 100 °C without the necessity to remove water. This reaction was also successfully conducted at the gram scale.
M. Hatano, C. Nishioka, A. Mimura, R. Kimura, Y. Okuda, T. Yamada, K. Sakata, Synlett, 2023, 34, 2508-2514.

A catalyst- and solvent-free, three-component synthesis of tetrasubstituted pyrroles in very good yields proceeds via a nucleophilic attack of primary amine on dialkyl acetylenedicarboxylate followed by Michael addition with β-nitrostyrene and successive intramolecular cyclization and aromatization. The method is highly atom economical and environmentally benign and can be scaled up.
G. Karthiyayini, D. G. Rajkumar, S. Nagarjan, V. Sridharan, C. U. Maheswari, Synthesis, 2023, 55, 1930-1938.

The use of DBSA (p-dodecylbenzenesulfonic acid) as a surfactant-type Brønsted acid catalyst enables selective esterifications in water. The reactions need neither dehydrating agents nor azeotropic removal of water. Instead, the catalyst and substrates in the present system assemble together through hydrophobic interactions to form devices for dehydration reactions.
K. Manabe, X.-M. Sun, S. Kobayashi, J. Am. Chem. Soc., 2001, 123, 10101-10102.

A robust and convenient molybdenum-catalyzed regioselective allylic amination of tertiary allylic carbonates provides α,α-disubstituted allylic amines in high yield with complete regioselectivity in ethanol as green solvent. Both aromatic and aliphatic amines react with various tertiary allylic alcohol derivatives. The catalyst can be recycled through simple centrifugation techniques.
S. Khan, M. Salman, Y. Wang, J. Zhang, A. Khan, J. Org. Chem., 2023, 88, 11992-11999.

The nontoxic, stable, environmentally benign, and easily available NaH₂PO₂ promotes reductive amination with E factors around 1. The reaction demonstrated a great compatibility with a wide range of functional groups.
F. Kliuev, A. Kuznetsov, O. I. Afanasyev, S. A. Runikhina, E. Kuchuk, E. Podyacheva, A. A. Tsygenkov, D. Chusov, Org. Lett., 2022, 24, 7717-7721.

The use of titanium silicalite (TS-1) in a packed-bed microreactor and H₂O₂ in methanol as solvent enable the formation of various pyridine N-oxides in very good yields. This flow process is a safer, greener, and more highly efficiency process than using a batch reactor. The device was used for over 800 hours of continuous operation while while the catalyst remained active.
S. Chen, S. Yang, H. Wang, Y. Niu, Z. Zhang, B. Qian, Synthesis, 2022, 54, 3999-4004.

The use of an ortho-naphthoquinone catalyst enables a biomimetic alcohol dehydrogenase (ADH)-like oxidation protocol as green alternative to existing stoichiometric and metal-catalyzed alcohol oxidation reactions. The developed organocatalytic aerobic oxidation protocol proceeds through an intramolecular 1,5-hydrogen atom transfer of naphthalene alkoxide intermediates.
J. Baek, T. Si, H. Y. Kim, K. Oh, Org. Lett., 2022, 24, 4982-4986.

Surfactant-Assisted Ozonolysis of Alkenes in Water: Mitigation of Frothing Using Coolade as a Low-Foaming Surfactant
S. Buntasana, J. Hayashi, P. Saetung, P. Klumphu, T. Vilaivan, P. Padungros, J. Org. Chem., 2022, 87, 6525-6540.

A mechanochemical solvent-free acyl Suzuki-Miyaura cross-coupling enables a highly chemoselective synthesis of ketones from widely available acyl chlorides and boronic acids. This chemoselective acylation reaction is conducted in the solid state, in the absence of potentially harmful solvents, and for a short reaction time.
J. Zhang, P. Zhang, Y. Ma, M. Szostak, Org. Lett., 2022, 24, 2338-2343.

Cost-effective and widely applicable protocols for controlled and predictably selective oxidation of methyl-/alkylarenes to corresponding value-added carbonyls have been developed, using a surfactant-based oxodiperoxo molybdenum catalyst in water and hydrogen peroxide (H₂O₂) as an environmentally benign green oxidant without any external base, additive, or cocatalyst.
P. Thiruvengetam, D. K. Chand, J. Org. Chem., 2022, 87, 4061-4077.

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.

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