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Durham University

Department of Chemistry

Multi-steps Organic Synthesis

Multistep synthesis is the process of taking a readily available compound (one you can buy) and converting it into the compound you need using chemical reactions. Multistep syntheses require more than one step (reaction), and so one or more intermediate compounds are formed along the way. This process is illustrated below:

In chemistry, the synthesis of most compounds of interest (Drugs, polymers, dyes…) cannot be done in a single step. Some synthesis are relatively short (2-4 steps), others can be very long (35-55 steps). For example, paracetamol (IUPAC: N-(4-hydroxyphenyl) ethanamide), a relatively simple molecule, can be prepared in one, two or three steps depending on the starting material you choose (what chemists call starting material is the very first chemical compound they will use to start a synthesis, the one they will use in the first step (or reaction) of the synthesis they want to make). Taxol (an anti-cancer drug) is a natural compound with a very complex structure whose total synthesis requires at least 40 steps.

1 to 3 steps

40 steps

How do chemists decide the chemical route they will use to prepare a compound? They use what is called retrosynthesis. Retro means going backward therefore in planning their synthesis, chemists start from the compound they want to make and cut it in smaller pieces, going backward, until they can reach the starting material they want to use (something they can easily buy and that is not too expensive).

Each of these smaller pieces corresponds to at least one reaction (or step). To clarify, let’s see an example with paracetamol:

Paracetamol contains an amide functional group and amide can be made from an amine and an acid chloride or an anhydride therefore we can prepare paracetamol in one step starting from para-aminophenol (IUPAC: 4-Aminophenol) and acetyl chloride (IUPAC: Ethanoyl chloride) or acetic anhydride (IUPAC: Ethanoic anhydride):

Paracetamol can also be prepared in three steps starting from phenol. How can we go backward from paracetamol to phenol? The first step is the same as above; we remove the amide to get to the free amino group and 4-Aminophenol. Then we have to think that the amino group can be prepared by reduction of a nitro group. The chemical compound that has an OH group and a nitro group on the benzene ring, facing each other is called para nitrophenol (IUPAC: 4- nitrophenol). The last step: how to insert a nitro group on the phenol ring? This can easily be done using an electrophilic aromatic substitution, something you have learned in school when you learned about the nitration of benzene. So see below how the retrosynthesis looks like:


Retrosynthesis (Backward synthesis) of paracetamol

Now see how the forward synthesis (the synthesis the chemist will perform in the lab) looks like compared to the retrosynthesis we just did:

However, how can we be sure that the nitration will take place on the carbon opposite the OH of phenol and not anywhere else?

The -OH can activate the benzene ring due to one of the lone pair of electrons on the oxygen group The donation of the oxygen's lone pair into the ring system increases the electron density around the ring. Phenol has more activating effect on some positions around the ring than others.That means that incoming groups will go into some positions much faster than they will into others.You will learn why at university

The -OH group has a 2,4-directing effect (also called ortho/para). That means that incoming groups (like the nitro group in our paracetamol example) will go into the 2- position (next door to the -OH group) or the 4- position (opposite the -OH group).

Remember: A chemical reactions rarely give only the product you want. Most of the time, the outcome of a chemical reaction is a mixture of compounds including the one you wanted to prepare. This is why it is not enough to learn how to do a chemical reaction, you also have to learn purification techniques that will alow you to retrieve the compound you want out of the mixture you obtained at the end of your reaction.

However, with careful planning and designing and tweaking of the conditions of reaction, chemists often manage to minimise the formation of side products (compounds they do not want) and maximise the formation of the compound for which the synthesis has been designed.