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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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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.

A silver-catalyzed double-decarboxylative protocol enables an efficient and pratical construction of chalcone derivatives via cascade coupling of substituted α-keto acids with cinnamic acids under mild and environmentally benign aqueous conditions.
N. Zhang, D. Yang, W. Wei, L. Yuan, F. Nie, L. Tian, H. Wang, J. Org. Chem., 2015, 80, 3258-3263.

An eco-friendly coupling of diaryl disulfides and aryl iodides under ligand-free conditions with copper nanopowder as catalyst and PEG-400 as solvent enables the synthesis of varous unsymmetrical diaryl in very good yields. The process is odour-free and the copper nanopowder-PEG-400 catalytic system can be directly reused for four repetitive cycles.
X.-m. Wu, G.-b. Yan, Synlett, 2015, 26, 537-542.

Nanoparticles formed from PdCl2 in the presence of tetramethyldisiloxane (TMDS) on water enable a mild and environmentally attractive dehalogenation of functionalized aryl halides. The reaction medium with the catalyst can be recycled.
A. Bhattacharjya, P. Klumphu, B. H. Lipshutz, Org. Lett., 2015, 17, 1122-1125.

A Cp*Ir complex bearing a functional bipyridonate ligand is a highly effective and versatile catalyst for the α-alkylation of ketones with primary alcohols under environmentally benign and mild conditions. Furthermore, this complex also exhibited a high level of catalytic activity for the α-methylation of ketones with methanol.
F. Li, J. Ma, N. Wang, J. Org. Chem., 2014, 79, 10447-10455.

An I2-mediated metal-free oxidative C-N bond formation enables a regioselective pyrazole synthesis. This practical and eco-friendly one-pot protocol provides a facile access to various di-, tri-, and tetrasubstituted (aryl, alkyl, and/or vinyl) pyrazoles from readily available α,β-unsaturated aldehydes/ketones and hydrazine salts without isolation of the less stable intermediates hydrazones.
X. Zhang, J. Kang, P. Niu, J. Wu, W. Yu, J. Chang, J. Org. Chem., 2014, 79, 10170-10178.

Vasicine, an abundantly available quinazoline alkaloid from the leaves of Adhatoda vasica, enables an efficient metal- and base-free reduction of nitroarenes to the corresponding anilines in water. The chemoselective method tolerates a wide range of reducible functional groups, such as ketones, nitriles, esters, halogens, and heterocyclic rings. Dinitroarenes are reduced selectively to the corresponding nitroanilines.
S. Sharma, M. Kumar, V. Kumar, N. Kumar, J. Org. Chem., 2014, 79, 9433-9439.

A general, efficient, and metal-free method for aerobic oxidation of primary benzylamines to the corresponding oximes in good yields is catalyzed by N,N′,N″-trihydroxyisocyanuric acid in the presence of acetaldoxime and water as solvent. This practical method uses air as economic and green oxidant, water as green solvent, and tolerates a wide range of substrates.
J. Yu, M. Lu, Synlett, 2014, 25, 1873-1878.

An 1,4-diazobicyclo[2.2.2]octane (DABCO) based ionic liquids were used as recyclable catalysts for the aza-Michael addition at room temperature without any organic solvent. A low loading of the very efficient [DABCO-PDO][OAc] catalyzed reactions of various amines with a wide range of α,β-unsaturated amides to afford products in very good yields within hours. Moreover, the catalyst could be reused up to eight times.
A. Ying, Z. Li, J. Yang, S. Liu, S. Xu, H. Yan, C. Wu, J. Org. Chem., 2014, 79, 6510-6516.

The use of tetrabutylammonium hydroxide as an efficient thia-Michael addition catalyst enables the conjugate addition of a broad range of mercaptan nucleophile to a very wide range of both classical and non-classical Michael acceptors. This methodology is especially attractive and operationally simple, as it generally proceeds with low catalytic loading and without excess reagent, and the produced products typically require no purification.
D. R. Nicponski, J. M. Marchi, Synthesis, 2014, 46, 1725-1730.

Diazotization of arylamines promoted by methanol with sodium nitrite and hydrochloric acid as diazotization agents followed by Sandmeyer borylation via a SN2Ar pathway provides a simple and green method to arylboronic acids and arylboronates.
C.-J. Zhao, D. Xue, Z.-H. Jia, C. Wang, J. Xiao, Synlett, 2014, 25, 1577-1584.

Green water can be used as hydrogen donor for a highly stereoselective and efficient transition-metal-free semihydrogenation of various internal diarylalkynes to E-alkenes. The reactions are conducted under convenient conditions and provide products in good to excellent yields, with broad substrate scope.
Z. Chen, M. Luo, Y. Wen, G. Luo, L. Liu, Org. Lett., 2014, 16, 3020-3023.

The use of a NaOtBu-O2 resulted in an efficient oxidative cleavage of vic-1,2-diols to form carboxylic acids in high yields. The present protocol is a green alternative to conventional transition metal based methods. Large-scale production with nonchromatographic purification is also possible.
S. M. Kim, D. W. Kim, J. W. Yang, Org. Lett., 2014, 16, 2876-2879.

An efficient synthesis of 2H-indazole derivatives in a one-pot three-component reaction of 2-chloro- and 2-bromobenzaldehydes, primary amines and sodium azide is catalyzed by copper(I) oxide nanoparticles (Cu2O-NP) under ligand-free conditions in polyethylene glycol (PEG 300) as a green solvent.
H. Sharghi, M. Aberi, Synlett, 2014, 25, 1111-1115.

An efficient method for the copper-catalyzed arylation of sulfonamides in water under ligand-free conditions offers high yields, simple workup procedure, and elimination of toxic materials.
M. Nasrollahzadeh, A. Ehsani, M. Maham, Synlett, 2014, 25, 505-508.

Gold-catalyzed cyclizations of diols and triols to the corresponding hetero- or spirocycles take place in an aqueous medium within nanomicelles, where the hydrophobic effect is operating, thereby driving the dehydrations, notwithstanding the surrounding water. By the addition of simple salts such as sodium chloride, reaction times and catalyst loadings can be significantly decreased.
S. R. K. Minkler, N. A. Isley, D. J. Lippincott, N. Krause, B. H. Lipshutz, Org. Lett., 2014, 16, 724-726.

A robust and green protocol for the reduction of functionalized nitroarenes to the corresponding primary amines relies on inexpensive zinc dust in water containing nanomicelles derived from the commercially available designer surfactant TPGS-750-M. This mild process takes place at room temperature and tolerates a wide range of functionalities including common protecting groups.
S. M. Kelly, B. H. Lipshutz, Org. Lett., 2014, 16, 98-101.

Various imidazolium salts bearing hydrophilic groups afford water-soluble NHC copper complexes. These copper complexes catalyze a selective oxidation of benzyl alcohols to the corresponding aldehydes in water at room temperature without the need for a base.
C. Chen, B. Liu, W. Chen, Synthesis, 2013, 45, 3387-3391.

An arylation of allylic and benzylic alcohols with diaryliodonium salts yields alkyl aryl ethers under mild and metal-free conditions. Phenols are arylated to diaryl ethers in good to excellent yields. The reaction employs diaryliodonium salts and sodium hydroxide in water at low temperature, and avoids the use of excess amounts of the coupling partners.
E. Lindstedt, R. Ghosh, B. Olofsson, Org. Lett., 2013, 15, 6070-6073.

A deep eutectic mixture of choline chloride and urea (1:2) is an efficient and ecofriendly catalyst for the one-pot synthesis of nitriles from aldehydes under solvent-free conditions under both conventional and microwave irradiation.  Nitriles were obtained in good to excellent yields.
U. B. Patil, S. S. Shendage, J. M. Nagarkar, Synthesis, 2013, 45, 3295-3299.

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