Green Chemistry

Are you familiar with the twelve points of Green Chemistry? No? Well, maybe it is because you are a medicinal chemist and not a process chemist. Green Chemistry, also known as Sustainable Chemistry, is a way of thinking when doing chemistry, seeking the reduction and prevention of pollution. There is some confusion about what is Green Chemistry and what is not, and why medicinal chemists do not use greener chemistry.

Let’s start by outlining the Twelve Principles of Green Chemistry:

1. It is better to prevent waste than to treat or clean up waste after it is formed.

2. Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product.

3. Wherever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment.

4. Chemical products should be designed to preserve efficacy of function while reducing toxicity.

5. The use of auxiliary substances (e.g. solvents, separation agents, etc.) should be made unnecessary wherever possible and, innocuous when used.

6. Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure.

7. A raw material or feedstock should be renewable rather than depleting wherever technically and economically practicable.

8. Reduce derivatives – Unnecessary derivatization (blocking group, protection/ deprotection, temporary modification) should be avoided whenever possible.

9. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.

10. Chemical products should be designed so that at the end of their function they do not persist in the environment and break down into innocuous degradation products.

11. Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances.

12. Substances and the form of a substance used in a chemical process should be chosen to minimize potential for chemical accidents, including releases, explosions, and fires.

This principles were formulated more than a decade ago, so for a chemist today they can look as common sense, but they were groundbreaking then. Some of them are clearly related to the Atom Economy concept (see here for a previous editorial related to this topic), others with security, etc.

For example, using water as solvent in a process follows the principles above (in fact, points 1, 5 and 12). But developing a reaction using water as solvent does not mean that you are developing a Green Chemistry reaction, because some points (for example, you are using lead as catalyst in the reaction) do not follow the Twelve Principles.

Which leads me to what sparked this editorial in the first place. Reviewing the papers for the Top Five section I came across a paper describing the direct synthesis of some purines. The paper came from a laboratory working in green chemical media and reactions, so I expected some interesting, fancy chemistry. What I found instead really infuriated me. Well, those people out there who know me will think that it is really not so difficult to infuriate me, but this article was too much in many aspects. I will reproduce one excerpt here:

Though significant attention has been received over the last several years, these cross-coupling reactions usually involve the following aspects: (a) expensive palladium, nickel, and complex ligands are employed as catalysis systems; (b) the preparation of organometallic reagents is usually conducted under rigorous reaction conditions (anhydrous, nitrogen atmosphere); (c) the reaction with metallic reagents usually requires multistep including protection of the sensitive functional groups (such as hydroxyl, amino, or imino group) in the substrates if necessary. This generates byproducts and wastes from reagents, solvents, and purification. Therefore, it is still of great importance to develop alternative methods for the preparation of 6-arylpurines.

I can’t disagree. Palladium and nickel are toxic, and its levels on APIs must be strictly controlled, though this is not so important in the research stages (which is, by the way, why many medicinal chemists do not think in terms of green chemistry). Ligands are sometimes complex and expensive. Reactions are often carried out under anhydrous conditions and under inert atmosphere, which is complicated and tedious. Sometimes the preparation of some scaffolds involve protection and deprotection of sensitive groups. As result of all the above sometimes you have byproducts. And yes, all that involves generating a stream of waste.

What really amazed me was the alternative proposed by the authors to a cross-coupling reaction:

The reactions, which were conducted using a 3-fold excess of AlCl3 in refluxing 1,2-dichloroethane, gave moderate to excellent product yields in 0.5 h.

Oh my. Much better than using a few milligrams of toxic Palladium, an expensive phosphine, etc. is to use three equivalents of AlCl3 and a halogenated solvent. Those chemists who have worked with AlCl3 (myself included) will know that this reagent is toxic, hazardous, must be handled in the absence of moisture (or at least as fast as possible to prevent the reagent fuming HCl) and that the destruction of the remanent is really tedious and dangerous. The waste is rich in aluminium salts and it has a pH which is usually around 1. To top it all, probably some ‘sensitive functional groups’ will not survive the reaction conditions or the quenching (also talking by first hand experience). So honestly, I simply cannot see the advantages. And this paper has been published in the Journal of Organic Chemistry !

As somebody said, ‘Finally, An Alternative to Palladium. About Time.’