How do organic chemists make anything?

It may be one of the most respected fields now, but early in its development organic chemistry came under a lot of fire because the field places a lower ‘emphasis’ on quantification than other fields. To be fair, this was a fair assessment as early organic chemistry was based heavily on trial-and-error and by extension, luck. Now they did get lucky sometimes and could stumble onto relatively simple structures as evidenced by Friedrich Wöhler’s synthesis of urea (1), but this luck cannot be relied upon when aiming to prepare nature’s complex products.

Structure of Urea once thought to be only produced by living organisms

Today, we have several complex molecules we use in our daily lives from pharmaceuticals to cosmetic products and everything in between and the question is: how are these things made anyway? Look at the structure of Lipitor, one of the best-selling drugs ever, below. Even if you don’t know anything about organic chemistry you can instinctively tell that nobody can stumble onto that product.

So how do organic chemists actually make anything? They use a process referred to as retrosynthetic analysis (2). But before that it had to be proven that these complex molecules could be made in the first place.

Organic chemistry escaped the so-called ‘Molecular Cooking’ era in 1944 when Robert Burns Woodward and his colleague William von Eggers Doering successfully synthesized the antimalarial quinine.3 Beginning with 3-hydroxybenzaldehyde, Woodward mapped out a way to quinotoxine because a German chemist Paul Rabe had claimed he had pioneered a way to convert quinotoxine to quinine (interestingly this wasn’t actually proven until around 2008 (4)).

Here’s the route Woodward and Doering used:

Total synthesis of Quinine

Now of course this pathway is too complex and costly to manufacture quinine for any feasible use at that time (this was during the world war after all), but it proved that any molecule could be made with proper planning and enough time (and sufficient money). He also went on to synthesize complex molecules like Chlorophyll, Reserpine, Cortisone, Cholesterol, Cephalosporin C and many other relevant compounds and is regarded as the father of modern organic synthesis (3).

His work set the stage for E. J. Corey’s framework on Retrosynthetic Analysis (5). Imagine you saw a beautiful piece of furniture with several moving parts at the mall, but when you ordered it, you were handed all the parts without any instructions on how it was to be assembled. You could of course try to assemble it by trial-and-error, and maybe you’d eventually succeed at assembling something, but it may not be very safe to use. More importantly, you have no way of replicating that feat if you had to assemble another furniture without doing more guesswork. This is the problem with forward synthesis.

On the other hand, if you had the assembled furniture delivered and had to take it apart temporarily, could strip it off piece-by-piece and note where each part belongs and this would make it much easier to assemble whenever you needed to. This is the core idea behind retrosynthetic analysis. By following the known principles of organic chemistry any molecule can be deconstructed into simple fragments then assembled.

While Woodwork was a master at constructing molecules intuitively, his work was limited to him and the strategies he used remained limited to him. Corey instead turned it into a systematic, logical algorithm that anyone could follow proving that synthesis required only strict logic for success.

To further expand upon this idea, I’ll be applying retrosynthetic analysis to a simple but popular drug: paracetamol. In retrosynthetic analysis, the molecule we aim to synthesize (in this case, paracetamol) is referred to as the ‘Target Molecule’ (TM) and breaking a bond in reverse is called a disconnection.

Looking at its structure, we can tell paracetamol is essentially a hydroxyl group linked to an amide by a benzene ring. Because we know that they can be (relatively) easy to make, we begin our disconnection from the C-N amide bond there leaving us with two parts: 4-aminophenol and an acetyl group which we can add to the nitrogen by the use of acetic anhydride.

Note the special type of double headed arrow I have used above. In retrosynthetic analysis, this means ‘is made from’ and is how we deconstruct molecules or show how a certain intermediate might be obtained. Another important point to keep in mind is that when you break a bond, you get theoretical fragments called synthons (5) like the acetyl fragment above. The actual chemicals you would then buy in a bottle to represent them (i.e acetic anhydride) are referred to as the synthetic equivalents (5).

While acetic anhydride is cheap and readily available, we can make our synthesis even cheaper by further breaking down 4-aminophenol into phenol and the amine.

Since we know from organic chemistry principles that the NH2 group synthon can be attached to a benzene ring by nitration, we can work back from 4-aminophenol to 4-nitrophenol to phenol.

Now we can play the whole thing forward.

And just like that, we have manufactured paracetamol from a bottle of phenol, isn’t organic chemistry fun? Not exactly, because you must also consider regioselectivity. When you nitrate phenol to make 4-nitrophenol, the reaction actually produces a mixture of two products: ortho-nitrophenol (nitro group next to the OH) and para-nitrophenol (nitro group opposite the OH). In practice, you would need to exploit the differences in physical properties of these two isomers to separate the unwanted ortho byproduct from the desired para byproduct before moving forward.

Summarily, Retrosynthetic analysis is not a very difficult concept to grasp. Of course, when it comes to complex molecules, more work has to be done, but sticking to the core organic chemistry principles and practicing a lot makes this process much easier.

Green Considerations

In modern organic chemistry, in addition to considering if a molecule can be made, a chemist must also consider how efficiently it can be made. This centres around two massive concepts that often guide modern synthesis planning namely Atom Economy and Step Economy. Atom economy is a metric that measures the efficiency of a chemical reaction by calculating the percentage of reactant atoms that are successfully incorporated into the final product (6). This concept, which was coined by Barry Trost, asks chemists to consider how many atoms from their starting materials actually end up in the final product and how end up as waste. In the paracetamol synthesis above, using acetic anhydride leaves behind one molecule of acetic acid as waste. We can reduce this waste by using the direct hydroquinone route to paracetamol which leaves behind water as the only by-product.

Step economy (credited to Paul Wender) is a principle focused on minimizing the total number of reaction steps needed to produce a target molecule (7). It basically argues that the most direct route to a chemical target is inherently the most practical, cost effective and environmentally friendly as an increase in the number of steps increases the yield loss and financial costs. For instance, if you have a 5-step synthesis and each step has an 80% yield, your overall yield is only about 33%. If a drug has 30 steps, even a 90% yield per step results in losing almost all your material. You may have noticed that the direct hydroquinone route also decreases the number of steps required to make paracetamol.

Now that you know how retrosynthetic analysis works, you can try applying it by taking a look at aspirin (acetylsalicylic acid) below:

As a hint, look at its two distinct functional groups and find the weakest link:

1. Identify the Target Molecule.
2. Perform a disconnection at the ester bond to find your two starting synthons.
3. Identify the cheap, commercially available synthetic equivalents you would buy in a bottle. (Think about how we added that acetyl group to paracetamol).
4. Work backward until you hit a simple, cheap starting material like benzene or phenol.

Have fun!

References

1 E. Kinne-Saffran and R. K. H. Kinne, American Journal of Nephrology, 1999, 19, 290–294.

2 Dr. Sarah Sattar Jabbar, London Journal of Research In Science: Natural and Formal, 2024, LJRS Volume 24, NA.

3 G. B. Kauffman, The Chemical Educator, 2004, 9, 172–176.

4 J. I. Seeman, Angew Chem Int Ed, 2007, 46, 1378–1413.

5 J. Wang, Y. Ji, Y. Tian and T. Fang, MS, DOI:10.61173/1ey5x303.

6 C.-J. Li and B. M. Trost, Proc. Natl. Acad. Sci. U.S.A., 2008, 105, 13197–13202.

7 P. A. Wender, V. A. Verma, T. J. Paxton and T. H. Pillow, Acc. Chem. Res., 2008, 41, 40–49.