Does classical organic synthesis have a future?

Green chemistry

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A traditional concept in process chemistry is the optimization of the space-time yield. From our current situation, this limited approach must be expanded, as e.g. toxic waste destroys natural resources and thus the livelihoods of future generations. In addition, it must be taken into account that some raw materials in the chemical industry are based on petroleum, which is not a renewable resource. The question therefore arises as to which alternatives are available or need to be developed. And it must be ensured that future generations can use these alternatives to the same extent. The concept of "sustainability" includes maintaining the long-term productivity of the environment so that future generations can also live on this planet. Sustainability therefore has environmental, economic and social dimensions.

Paul Anastas of the EPA (Environmental Protection Agency of the USA) has drawn up 12 points of focus on how sustainability can be achieved in the manufacture of chemicals and chemical products - the "Principles of Green Chemistry":

  1. Avoidance of waste instead of its disposal
  2. Atomic Economy and Atomic Efficiency
  3. Use of more harmless and less toxic chemicals
  4. Development of safe products
  5. Use of non-hazardous solvents and auxiliary materials
  6. Better energy efficiency
  7. Preferential use of renewable raw materials
  8. Shorter synthetic routes
  9. Catalysts instead of stoichiometric reagents
  10. Products should be degradable in the environment
  11. Analytical methods for monitoring pollution
  12. Safe processes from the ground up

The implementation of these principles of green chemistry definitely requires a certain amount of investment, as many of the current, often very cost-effective, chemical processes have to be redeveloped. But in times when raw materials are becoming scarce (for example, certain transition metals are only available in limited quantities) and energy costs rise, the financial outlay for the new development will be recovered at some point. This means that the optimized processes will be cheaper in the future than the traditional methods. Thus, the development of green methods can be seen as an investment in the future, which also helps to ensure that production remains compliant with future legal regulations.

A typical chemical process creates products and waste from raw materials such as starting materials, solvents and reagents. When reagents and solvents are recycled, the mass flows are significantly different:

So the amount of waste can be reduced if most of the reagents and solvents are recyclable. For example, catalysts and reagents such as acids and bases could be bound to a solid phase, regenerated after simple filtration and then reused. In large-scale products, heterogeneous catalysts remain stationary, whereas starting material is added continuously and the product is continuously removed (e.g. by distillation).

The mass efficiency of chemical processes can be assessed with the help of the E-factor (English: Environmental factor):

An ideal E-factor of 0 is almost reached in the refining of petroleum; Factors between 1 and 50 are normal for fine chemical production. Typical E-factors for pharmaceutical products are between 25 and 100. Attention: Water is not included in the calculation, because otherwise the E-factors will be significantly increased during extractions. However, inorganic and organic residues in the water must be taken into account. Sometimes it is easier to calculate e-factors from a different perspective, as the losses and exact waste streams are often difficult to assess.

The main problem, however, is that the E-factor does not take into account the toxicity of the waste. A correction factor (an "unfriendliness factor" Q) would be 1 if the waste has no impact on the environment; less than 1 if the waste is recyclable or used in another product; or greater than 1 if the waste is dangerous (toxic). However, such discussions have so far been rather at an early stage, which is why uncorrected E-factors are still used in order to compare chemical processes quantitatively with one another.

Another approach to calculating the efficiency of chemical reactions is what is known as atomic economy or atomic efficiency:

Atomic efficiency is a purely theoretical value that does not include solvent or actual yield. However, an experimental atomic efficiency can be calculated by multiplying the chemical yield by the theoretical atomic efficiency. Nonetheless, this discussion remains rather in a quantitative framework, since it does not take into account how toxic products and reagents are. But "atom economy" as a term can certainly be used to describe reactions.

Concrete reactions show two main points of attack on which "green chemistry" focuses: choice of solvent and the development of catalyzed reactions. For example, the Woodward reaction in the production of steroids could be replaced thanks to the development of catalyzed variants. In the original reaction, the large amount of silver salts used is also an economic factor:

Woodward reaction

The silver salts can by stoichiometric amounts of OsO4 replaced, but osmium tetroxide is both very toxic and costly. First a catalyzed variant with N-Methylmorpholine-N-Oxide as a stoichiometric oxidizer can be seen as a green reaction:

Upjohn dihydroxylation

In some new protocols, H2O2 used to the nascent N-To reoxidize methylmorpholine, which means that this reagent can also be used in catalytic amounts. Looking at the atomic efficiency, it is noticeable that H2O as a stoichiometric by-product is significantly better than N- is ethylmorpholine. It is also worth mentioning that reaction systems have been developed in which the osmium catalyst is bound to a solid matrix, which makes it easier to separate it from the products and to reuse it. Another advantage of such a polymer-bound catalyst is the avoidance of toxic traces of transition metals - e.g. in pharmaceutical products.

An important point, however, is the choice of solvent, as this is the main component (approx. 90%) of chemical reaction systems. Chlorinated solvents should be avoided as many of these solvents are toxic, volatile and contribute to the depletion of the ozone layer. Alternative solvents would be ionic liquids, for example, which are non-volatile and allow non-aqueous reaction media of different polarity. Ionic liquids have great potential because systems can be developed in which products can be separated from the solvent by extraction or distillation. If a catalyst remains in the ionic liquid, both solvent and catalyst can theoretically be recycled. The solvent of choice for green chemistry, however, is water - a non-toxic liquid with limited chemical compatibility. On the one hand, specific Diels-Alder cycloadditions are even accelerated in water; on the other hand, some reagents such as organometals are incompatible with water. This opens up a large field of activity to find reactions that lead to the desired products in aqueous solutions. A brief overview can be found here: S. Varma, Clean Chemical Synthesis in Water, Org. Chem. Highlights2007, February 1. Chemical reactions that take place dry (without solvents) or in supercritical CO2 expire can also be viewed as green alternatives. Other possibilities for improvement include, for example, replacing benzene with toluene (as a less toxic alternative) or using solvents that are quickly broken down by microorganisms.

Some of the advances made in recent years in developing green alternatives to classic reactions have been astonishing. Examples of this can be found in the literature section of the English-language page (Green Chemistry), which is continuously updated. A good introduction to green chemistry - on which this text is partially based - with a focus on catalysis offers a book edited by Sheldon, Arends and Hanefeld (Green Chemistry and Catalysis, Wiley-VCH Weinheim, 2007, 1-47.).


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

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