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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

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

Recent Literature

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In the presence of [Cp*Ir(6,6'-(OH)2bpy)(H2O)][OTf]2, an acceptorless dehydrogenative cyclization of o-aminobenzyl alcohols with ketones provided quinolines in high yields.
R. Wang, H. Fan, W. Zhao, F. Li, Org. Lett., 2016, 18, 3558-3561.

A convenient and efficient synthesis of thiosulfonates in very good yields from thiols and sodium sulfinates involves iron(III)-catalyzed formation of sulfenyl and sulfonyl radicals in situ under aerobic conditions and their subsequent cross-coupling. The utilization of readily available, nontoxic, and inexpensive iron(III) as a catalyst and atmospheric oxygen as an oxidant makes this process green and sustainable.
T. Keshari, R. Kapoorr, L. D. S. Yadav, Synlett, 2016, 27, 1878-1882.

Well-defined Co(II) complexes stabilized by a PCP ligand catalyze efficient alkylations of aromatic amines by primary alcohols into mono-N-alkylated amines in very good yields. The inexpensive, earth-abundant nonprecious metal catalysts make this acceptorless alcohol dehydrogenation concept environmentally benign.
M. Mastalir, G. Tomsu, E. Pittenauer, G. Allmaier, K. Kirchner, Org. Lett., 2016, 18, 3462-3465.

A phosphorous acid promoted alkyne-aldehyde hydration-condensation enables a simple and environmentally benign synthesis of chalcones in high to excellent yields in an oil/water two-phase system.
Y. Zhou, Z. Li, X. Yang, X. Chen, M. Li, T. Chen, S.-F. Yin, Synthesis, 2016, 48, 231-237.

An efficient method for the 2-hydroxylation of 1,3-diketones by using inexpensive atmospheric oxygen as an oxidant under transition-metal-free and ecofriendly conditions provides products in high yields.
Z. Li, T. Li, J. Li, L. He, X. Jia, J. Yang, Synlett, 2015, 26, 2863-2865.

Using copper-NHC complexes, the reaction of nitriles with aminoalcohols provided 2-substituted oxazolines under milder and less wasteful conditions than those of previously reported methods.
M. Trose, F. Lazreg, M. Lesieur, C. S. J. Cazin, J. Org. Chem., 2015, 80, 9910-9914.

An efficient bismuth tribromide catalyzed oxidation of various alcohols with aqueous hydrogen peroxide provides carbonyl compounds in good yields.
M.-k. Han, S. Kim, S. T. Kim, J. C. Lee, Synlett, 2015, 26, 2434-2436.

2-phenoxycarbonyl-4,5-dichloropyridazin-3(2H)-one is a solid stable carbonyl source that is a recyclable. The reagent enables the synthesis of benzo[d]thiazol-2(3H)-ones, benzo[d]oxazol-2(3H)-ones, and benzo[d]imidazol-2(3H)-ones using in one pot out under neutral or acidic conditions to give the corresponding heterocycles in very good yields.
K. E. Ryu, B. R. Kim, G. H. Sung, H. J. Yoon, Y.-J. Yoon, Synlett, 2015, 26, 1985-1990.

In three odorless methods for the thioarylation and thioalkylation of different nitroarenes using alkyl halides (Br, Cl), triphenyltin chloride, and arylboronic acids as the coupling partners, Na2S2O35H2O, S8/KF, and S8/NaOH systems are found to be effective sources of sulfur in the presence of copper salts. The methods offer use of green solvents, inexpensive catalysts, and user-friendly starting materials.
A. Rostami, A. Rostami, A. Ghaderi, J. Org. Chem., 2015, 80, 8694-8704.

Two chromatography-free and eco-friendly protocols for tosylation and mesylation of phenols offer simplicity, short reaction time, mild conditions, and environmental friendliness. The reactions transform a broad range of substrates in excellent yields.
X. Lei, A. Jalla, M. A. A. Shama, J. M. Stafford, B. Cao, Synthesis, 2015, 47, 2578-2585.

Iodine-catalyzed cascade reactions of substituted thiophenols with alkynes under metal- and solvent-free conditions enable the synthesis of benzothiophene derivatives in good yields. Such an efficient, economical, and green transformation should provide an attractive approach to various benzothiophenes.
K. Yan, S. Yang, M. Zhang, W. Wei, Y. Liu, L. Tian, H. Wang, Synlett, 2015, 26, 1890-1894.

Use of uronium salt (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU) as a coupling reagent, 2,6-lutidine, and TPGS-750-M enabeles a general, mild, and environmentally responsible method for the formation of amide/peptide bonds in an aqueous micellar medium.  The aqueous reaction medium is recyclable leading to low E Factors.
C. M. Gabriel, M. Keener, F. Gallou, B. H. Lipshutz, Org. Lett., 2015, 17, 3968-3971.

An efficient and environmentally friendly phosphoric acid mediated decarboxylative coupling of sodium sulfinates with phenylpropiolic acids provides vinyl sulfones.
G. Rong, J. Mao, H. Yan, Y. Zheng, G. Zhang, J. Org. Chem., 2015, 80, 7652-7657.

A copper-catalyzed annulation of 1,3-dicarbonyl compound with diethylene glycol gives 2,3-disubstituted furans in the presence of tert-butyl peroxide (TBHP) via a sequential O- and C- functionalization of β-ketoester by diethylene glycol. Diethylene glycol serves as a environmentally friendly and cheap substitute of ethyne, that releases H2O and alcohol as clean wastes.
J.-T. Yu, B. Shi, H. Peng, S. Sun, H. Chu, Y. Jiang, J. Cheng, Org. Lett., 2015, 17, 3643-3645.

An efficient domino one-pot strategy for the synthesis of isobenzofuran-1(3H)-ones includes [Cu]-catalyzed intermolecular cyanation of o-bromobenzyl alcohols, in situ intramolecular nucleophilic attack and hydrolysis. This reaction can successfully be carried out under environmentally benign conditions, using water as sole green solvent.
L. Mahendar, G. Satyanarayana, J. Org. Chem., 2015, 80, 7089-7098.

The use of quaternary ammonium salts, which are environmental friendly, inexpensive, and recyclable enables a simple and highly efficient multicomponent reaction of aldehydes or ketones with amines and diethyl or triethyl phosphite to give the corresponding α-aminophosphonates in excellent yields at room temperature.
Y.-Q. Yu, D.-Z. Xu, Synthesis, 2015, 47, 1869-1876.

Sodium sulfide in combination with iron(III) chloride hexahydrate promote an unbalanced redox condensation reaction between o-nitroanilines and alcohols, leading to benzimidazole and quinoxaline heterocycles. Beside the role as a precursor for an iron-sulfur catalyst, hydrated sodium sulfide is also an excellent noncompetitive, multi-electron reducing agent.
T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Synthesis, 2015, 47, 1741-1748.

An efficient catalyst- and solvent-free addition of secondary phosphine chalcogenides to diverse aldehydes enables an almost quantitative synthesis of tertiary α-hydroxyphosphine chalcogenides under mild conditions (20-52 C, from 10 min to 5 h).
N. K. Gusarova, N. I. Ivanova, P. A. Volkov, K. O. Khrapova, L. I. Larina, V. I. Smirnov, T. N. Borodina, B. A. Trofimov, Synthesis, 2015, 47, 1611-1622.

Pyrrolidinine-thioxotetrahydropyrimidinone derivatives were tested for their catalytic properties in various asymmetric organic transformations. These catalysts could efficiently catalyze the reactions in brine, without the use of organic solvent, and by employing an almost stoichiometric amount of reagents. Thus, the products were isolated by simple extractions in excellent yields, diastereoselectivities, and enantioselectivities.
N. Kaplaneris, G. Koutoulogenis, M. Raftopoulou, C. G. Kokotos, J. Org. Chem., 2015, 80, 5464-5473.

N-functionalized amino acids serve as powerful N,O-bidentate ligands in an aerobic copper/TEMPO-catalyzed system for the oxidation of benzylic alcohols in water. Under optimized reaction conditions, a broad range of primary and secondary benzylic alcohols have been efficiently converted into carbonyl compounds in very good yields.
G. Zhang, J. Lei, X. Han, Y. Luan, C. Ding, S. Shan, Synlett, 2015, 26, 779-784.

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