Retrosynthetic Analysis: Thinking Backwards From the Target

The basic move

A disconnection is a bond broken on paper, in the reverse direction to a real reaction. It produces fragments called synthons, which are idealised charged species, and each synthon corresponds to a real reagent equivalent.

For example, disconnecting the bond between the carbonyl carbon and its neighbour in a secondary alcohol gives a carbanion synthon and a carbonyl synthon. The carbanion's real equivalent is a Grignard reagent, and the carbonyl's is an aldehyde. That is the forward reaction, recognised backwards.

Where to disconnect

Good disconnections share features worth learning to recognise:

• At a carbon–heteroatom bond, which is usually easy to form.
• Next to a functional group, since functional groups are what activate bonds for formation.
• At a branch point, which simplifies the skeleton most.
• Symmetrically, where the target has symmetry, since two identical fragments halve the work.
• To give fragments of comparable size, which converges faster than removing one carbon at a time.

Common relationships and what they suggest

The 1,3- and 1,5-dicarbonyl patterns are worth memorising as recognition triggers. Seeing that spacing in a target is a strong hint that a Claisen or a Michael was involved.

Functional group interconversion

Sometimes the target has no bond worth disconnecting directly. The move then is to convert a functional group into one that does allow a good disconnection.

A carboxylic acid, for instance, offers few useful disconnections directly, but converting it retrosynthetically to a nitrile opens a straightforward substitution disconnection. Recognising when to interconvert before disconnecting is what separates a fluent answer from a stuck one.

Working the problem

1. Draw the target clearly and number the carbons if the skeleton is complex.
2. Identify the functional groups and their relative positions.
3. Look for a recognisable relationship from the table above.
4. Disconnect, and immediately write the forward reaction beneath.
5. Repeat on each fragment until you reach available starting materials.
6. Write the synthesis forwards, checking selectivity and whether protection is needed at each step.

Step six is where marks are won and lost. A route that is correct on paper but ignores a competing reaction, or fails to protect a sensitive group, is incomplete.

Frequently asked questions

How do I know which of several disconnections is best?

Prefer the one that simplifies most, corresponds to the most reliable reaction, and produces fragments most likely to be commercially available. Where two are equally good, either is acceptable if the forward route works.

What is the difference between a synthon and a reagent?

A synthon is an idealised fragment, often a charged species with no independent existence. The reagent equivalent is the real compound that behaves as that synthon — a Grignard reagent standing in for a carbanion, for example.

Do I always have to reach commercially available starting materials?

In an exam, reach something simple and recognisable. In practice the endpoint is whatever can be bought or is already in hand.

How do I get faster at this?

By building a mental library of what each reaction produces, then recognising those products in targets. The recognition is the skill; the disconnection follows automatically once the pattern is seen.