Molecular blueprints: the synthesis of ibuprofen

This is the second and last article in a two-part series on retrosynthesis. First article: Molecular Blueprints: The Art of Synthetic Planning.

Introduction

In the second article in this series on synthetic planning, the retrosynthetic techniques discussed previously are applied to the synthesis of ibuprofen. Developed by the Boots company in the 1950s and 1960s as an analogue of aspirin, ibuprofen had been taken by more than 100 million people in over 120 countries by 1985. Widely used for pain relief and as an anti-inflammatory, the chemical importance of ibuprofen cannot be overstated.

Retrosynthetic analysis of ibuprofen

In the previous article, all the syntheses of aspirin shown were achievable in two steps due to its relatively simple molecular structure. However, ibuprofen requires a multistep synthesis to build up to its increased complexity.

A useful FGI at the outset would be to convert the carboxylic acid into a nitrile, as this group can later be readily converted back using acid and water. To build the isobutyl fragment, a Friedel–Crafts acylation could be employed, avoiding unwanted side reactions which come from Friedel–Crafts alkylation. Lastly, the resulting ketone product can be easily reduced using a Clemmensen reduction (Zn/Hg) to remove the carbonyl group altogether.

Once a retrosynthetic pathway has been proposed, the next step is to identify a suitable starting material — typically something cheap and readily available. For this synthesis, a sensible starting material would be benzene.

As shown in Figure 1, the disconnection strategy targets the isobutyl portion of the side chain. To install the remaining carbon framework, a second Friedel–Crafts acylation will work nicely (Figure 2).

At this stage, two challenges remain. Firstly, the molecule is missing a carbon atom — this is not an issue, as the earlier retrosynthetic analysis shows the addition of a nitrile group which will extend the chain. The next question is how to convert a ketone to a nitrile group.

This sequence begins with a reduction of the ketone to form a secondary alcohol using sodium borohydride (NaBH₄). Since alcohols are poor leaving groups, direct nucleophilic substitution (SN2) is not possible. Instead, an Appel reaction can be used to convert the alcohol into a halide, creating a stable leaving group.

An Appel reaction proceeds via an SN2-like mechanism using triphenylphosphine (PPh₃). The reason the alcohol is now a good leaving group is due to the formation of a phosphorus–oxygen double bond, which drives the reaction forward. This now allows substitution using NaCN, after which acid and water can be added to form the final product (Figure 3).

Conclusion

Together, the two articles in the Molecular Blueprints series highlight the power of retrosynthetic analysis in guiding organic synthesis. This technique forms the foundation for one of the most active areas of modern chemistry: total natural product synthesis.

Written by Antony Lee

Related article: Exploring ibuprofen