Multi Step Organic Synthesis

Multi step organic synthesis is the process of converting a starting compound into a target compound through a sequence of separate reactions, each one changing (or introducing) a functional group. In A Level chemistry you will rarely be able to jump directly from a starting material to the final product in one reaction; instead you build up the molecule piece by piece, using reactions you already know from earlier topics such as halogenation, oxidation, esterification and reduction.

The skill being tested is not memorising one new reaction. It is combining reactions you already know, in the right order, with the right reagents and conditions, to reach a specified product.

A synthetic route has to do more than just "get to the product". A well planned route:

• Uses the fewest reasonable steps, since every extra step lowers the overall yield.
• Introduces functional groups in an order that does not destroy a group installed earlier.
• Avoids unwanted side reactions, such as further substitution or over oxidation.
• Accounts for any stereochemistry required in the final product.

Because each step rarely gives 100% conversion, the overall yield of a multi step synthesis falls quickly as the number of steps increases. If three steps each give 80% yield, the overall yield is only \( 0.80 \times 0.80 \times 0.80 = 0.512 \), or about 51%. For any individual step, percentage yield is calculated with:

\( \%\, yield = \dfrac{m_{actual}}{m_{theoretical}} \times 100 \)

where \( m_{actual} \) is the mass actually obtained and \( m_{theoretical} \) is the maximum possible mass predicted from the balanced equation.

The most reliable planning method is retrosynthetic thinking: start at the product and ask "what functional group was here immediately before this one, and what single reaction could have produced it?" Repeat this question, moving backwards, until you reach a starting material that is either given or is a simple, commonly available compound.

As you work backwards, keep a running list of the functional group interconversions available to you, for example:

• Alkene to alcohol (electrophilic addition of steam or water).
• Alcohol to carboxylic acid (oxidation with acidified dichromate).
• Carboxylic acid to ester (esterification with an alcohol, or via an acyl chloride for a faster reaction). This step connects directly to carboxylic acids, acyl chlorides and esters.
• Halogenoalkane to amine (nucleophilic substitution with excess ammonia).
• Nitro group to amine (reduction), a key step for building nitrogen containing products discussed further in amines, amides and amino acids.

Once the backward chain is complete, read it forwards. That forward reading is your synthetic route.

Suppose the target is an aromatic amide, but you are only given benzene as a starting material. Working backwards: an amide comes from an amine reacting with an acyl chloride; the amine comes from reducing a nitro group; the nitro group comes from nitrating benzene. Read forwards, the route is:

Notice how each arrow represents one functional group interconversion, and the reagents chosen for step two (tin and hydrochloric acid, then reflux) do not interfere with the nitro group already present until that step is meant to change it. This ordering matters: attempting the reduction before the nitration would make no sense, since there would be no nitro group yet to reduce.

A second common route type starts from an alkene and ends at an ester.

1. Alkene reacts with steam over a phosphoric acid catalyst to give an alcohol (electrophilic addition).
2. The alcohol is oxidised with excess acidified potassium dichromate under reflux to give a carboxylic acid.
3. The carboxylic acid is heated with a second alcohol and a small amount of concentrated sulfuric acid catalyst to give an ester and water.

If instead a faster, more complete reaction is wanted for the final step, the carboxylic acid can first be converted to an acyl chloride, which then reacts rapidly with an alcohol at room temperature. Both approaches are explored in more depth in carboxylic acids, acyl chlorides and esters, and the general principles of building larger repeating chains from such esters lead into condensation polymers.

• Wrong order of steps. Introducing a reactive group too early can cause it to interfere with a later reaction, so always check whether an earlier functional group survives the next reagent.
• Vague reagents or conditions. Examiners expect a specific reagent (not just "an oxidising agent") and the correct condition, such as reflux versus distillation.
• Ignoring stereochemistry. Some routes create a molecule with a chiral centre, producing a mixture of optical isomers rather than a single pure product; this is covered separately in chirality and optical isomers.
• Forgetting purification. Every organic step usually needs a purification technique afterwards, such as recrystallisation or distillation, before the next reaction can be carried out on a pure sample.

When faced with an unfamiliar starting material and target product, follow this checklist:

1. Draw both structures and highlight every functional group present in each.
2. Compare the two lists of functional groups to see what needs to appear, disappear or move.
3. Work backwards one functional group interconversion at a time until you reach the given starting material.
4. Write the route forwards, stating a specific reagent and condition for every arrow.
5. Check the order again: could an earlier reagent damage a group installed in a later step?

With practice, recognising these functional group interconversions becomes automatic, and multi step synthesis questions turn into a straightforward matter of sequencing reactions you already know.

Related lessons

• Uk A Level Chemistry