Wizards exist in real life, beyond the films and books of Harry Potter. They cook willow bark extract in car battery acid and wood alcohol and convert it into a pleasant-smelling component of candy or of a rubbing compound. In their glassware, petroleum products turn into life-saving medicines.
The vastly underrated wizards we are referring to are organic chemists who specialize in synthesis. In their quest to create new combinations of atoms or in their attempts to find ways of producing natural compounds, they craft new reactions, constantly combining creativity with the scientific method. Even if somehow we were not interested in creating organic compounds (and in doing so, saying goodbye to pharmaceuticals, plastics, fabrics, oils, and perfumes), synthesis would still be needed to verify chemical structure.
Here’s why. When chemists isolate a new compound, they determine its structure using various spectroscopic techniques: mass spectroscopy, which identifies the unknown’s molecular formula; infrared spectroscopy, which identifies key functional groups and nuclear magnetic resonance which reveals the local chemical environment of each atom within a molecule. From the spectral analysis a model is constructed. Then a compound is synthesized step-by-step to test the validity of the proposed structure. If the synthesized product and unknown natural product have identical physical, chemical and spectral properties, the model is in all likelihood valid.
But just exactly how do organic chemists assemble exotic molecules or carbon-copies of evolutionary products? As an example, let’s use sildenafil, the key part of sildenafil citrate, also known as Viagra. Nitric oxide(NO) is released from the nerve endings of a sexually stimulated male, leading to the production of cyclic guanosine monophosphate(cGMP) which relaxes penis vessels, allowing blood flow to increase. But enzymes eventually break down the messenger, allowing some blood to flow out of the penis. Viagra, molecular impostors of cGMP, relieve men with erectile dysfunction by competitively binding to the enzyme phosphodiesterase type 5, which then cannot attack its intended prey. The end result is a prolonged erection in the presence of sexual stimulation.
The following is the structure of sildenafil.
The parts I’ve colored are essentially its four basic building blocks. Of course without knowing the chemistry of the components’ precursors, the thermodynamic stability of in-between products and anticipation of side reactions, they will never come together to give us our target molecule. Even then, because specific conditions such as pH, temperature and solvent-type are such important factors, it takes a lot of tweaking, luck and lateral thinking to come up with a sequence of reactions that will yield a respectable amount of final product. In the synthesis that I’ve chosen to highlight (it’s not the only viable method), there are nine steps. If each step was only 90% efficient, then the overall process would only have a 0.909 = 39% yield. Sixty one percent of the original mass of reactants would be wasted. As Peter J Dunn outlines in a few of his review papers, the commercial synthesis of Viagra is highly efficient and also clean environmentally.
The red part of the molecule that features a pentagon-shape with two nitrogen atoms and two additional nitrogen atoms is a pyrazole-derivative. Before fusing into the final Viagra structure, the reactant, dubbed pyrazole 4 is shown to the left.
It’s so key to the overall production of Viagra that several pharmaceutical companies have patented unique ways of producing the compound. In one method, a colorless and rare food additive with a smell like that of nail-polish remover, thanks to alkaline conditions, attacks the electron loving-site of the double-bonded carbon in oxalic acid diester. (Also known as ethyl oxalate, it’s sold to academics for $58/kg.) 
The fused product, accompanied by the production of alcohol, has to age like certain wines to its more thermodynamically stable product, shown to the right of the equilibrium sign.
The two nucleophilic nitrogens of methylhydrazine subsequently attack two C=O groups of the same molecule to create the pyrazole. In the two final steps that create pyrazole 4, nitric acid and ammonia add two more nitrogen atoms, which are needed keys to latch on to the “purple part” of the Viagra molecule.
Pyrazole 4’s nitro group(NO2) is reduced with hydrogen gas to an amino group(NH2). This will fuse with a molecule created by three common chemicals combining in a chlorosulphonation reaction. What happens, essentially, is that the chlorine atom gets bumped out by the more basic of the two nitrogen atoms in the piperazine ring while the rest of the chlorosulfuric acid (ClSO3H) molecule attacks the aromatic ring of 2-ethoxybenzoic acid, a molecule sometimes used as a dental cement.
In the second last step, CDI (carbonyldiimidazole or Staab’s reagent) is used to link the previously constructed molecule with pyrazole 4. The idea of using CDI comes from the fact that it helps link amino acids (the amino part to the carboxylic part) in creating peptides or simple proteins. Finally we get a similar reaction of an amino group combining with an amino group, but this time the attack is intramolecular, closing a second nitrogen ring to create sildenafil.
Viagra is actually a citrate salt which is water-soluble, and this is obtained simply by reacting sildenafil, a base, with citric acid in a reaction that is 100% efficient. The last three key steps of the reaction make use of only one solvent, making the process environmentally friendly. Solvents have to be discarded, so by using less, pharmaceutical companies create less waste. The overall environmental impact of Viagra’s industrial production is low with just 6 kg of waste per kg of product compared with an industry average of 25 to100 Kg. In 2003, for their efforts towards the efficient production of Viagra, Pfizer received the United Kingdom Award for Green Chemical Technology ("Best Process" category).
- Peter J. Dunn. Synthesis of Commercial Phosphodiesterase(V) Inhibitors. Organic Process Research&Development 2005 9, 88-97
- Peter J. Dunn, Stephen Galvin and Kevin Hettenbach The development of an environmentally benign synthesis of sildenafil citrate (Viagra™) and its assessment by Green Chemistry metrics. Green Chem. , 2004 , 6 , 43 – 48
