Green Chemistry Principle #8: Reduce Derivatives

By Trevor Janes, Member-at-Large for the GCI

8. Unnecessary derivatization (e.g. installation/removal of use protecting groups) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste.

In Video #8, Cynthia and Devon look at one common example of derivatization, which is the use of protecting groups in chemical reactions. To help illustrate the concept of a protecting group, they use toy building blocks.

In this blog post, I will use cartoons such as the one shown below (a specific example of the use of protecting groups will be shown at the end of this post).

Principle 8 - unselective reaction

Figure 1 An unselective reaction.

In Figure 1, the starting material contains two reactive sites, represented by U-shaped slots. We only want the slot on the right to react with the reagent, shown as red circles. The starting material is reacted with the reagent in order to make the desired product, but an undesired product also forms, because both U-shaped slots react with the red circle. In other words, Figure 1 shows an unselective reaction because a mixture of products is made.

Formation of the undesired product can be avoided by carrying out a protection reaction before using the red reagent, and then carrying out a final deprotection reaction. This sequence of reactions is shown in Figure 2.

Principle 8 - selectivity through protecting groups

Figure 2 A selective reaction through the use of a protecting group, which temporarily blocks the reactive site on the left side. 

 

Figure 2 shows how a selective reaction is traditionally done – through the use of a temporary block, known as a protecting group. The starting material can be protected by blocking one of the reactive sites, represented by the blue rectangle covering the U-shaped slot on the left. This intermediate only has one reactive site left, so the second reaction with the red reagent can only happen at the empty U-shaped slot on the right. To get the same desired product as in Figure 1, the third and final deprotection step is carried out, which removes the protecting group.

Principle 8 - waste from protecting groups

Figure 3 The waste created by all three reactions in Figure 2.

Even though the product from Figure 2 is the desired product, we had to do three reactions to only make one change, which is inefficient. Also, each step generates waste products (shown underneath each reaction arrow in the above cartoon) , which are depicted in Figure 3.

Protecting groups are a useful tool that chemists use to make the molecules, because we often need to carry out selective reactions on a molecule that has multiple of the same reactive sites. However, as we have talked about here, they are also inefficient and wasteful.

An active area of research is the development of more selective reactions, which eliminate the need to use protecting groups altogether.[1] Selective reactions use slight differences in a molecule’s chemistry to make a reaction happen at only the desired reactive site. This is very similar to the installation of the protecting group in Figure 2.

As more and more highly selective reactions are discovered, our syntheses can be made more efficient by reducing the number of steps required and the amount of waste produced. Looking ahead, protecting groups will be less and less necessary – and that’s a good thing!

 

Appendix – Example from Real Chemistry

A simple, specific example of the use of protecting groups[2] is shown below. Both oxygen-containing sites are reactive, but we only want the one on the left side to react in this case. The first reaction is the installation of the protecting group, (CH3)3SiCl, on the OH oxygen only, protecting the right side. The second reaction shows the reagent, CH3CH2CH2MgBr (for those curious, this is called a Grignard Reagent), which now reacts with just the ketone C=O site on the left, adding the desired new CH3CH2CH2 segment. The last step shows a combination of removing the protecting group to return the OH group, and also removing the [MgBr] segment of the reagent with the help of acid (shown as H3O+), which leaves the desired product with a CH3CH2CH2 chain added only on one side of the molecule.

Principle 8 - real protecting group use in chemistry

This example of a selective reaction uses a protecting group, but this requires 3 steps to only make 1 change. Instead, we can eliminate the need for protecting groups by designing new and more selective reactions that are much more efficient.

References:

[1] I. S. Young and P. S. Baran, Nature Chem. 2009, 1, 193

[2] R. J. Ouellette and J. D. Rawn, in Organic Chemistry, 2014, Elsevier, Boston pp 491-534.