Question 9.5: Propose a synthesis of 4-chloro-2-propylbenzenesulfonic acid...
Synthesizing a Polysubstituted Benzene
Propose a synthesis of 4-chloro-2-propylbenzenesulfonic acid from benzene.
S t r a t e g y
Draw the target molecule, identify its substituents, and recall how each of the three can be introduced. Then plan retrosynthetically.
The three substituents on the ring are a chlorine, a propyl group, and a sulfonic acid group. A chlorine can be introduced by chlorination with Cl_2/FeCl_3, a propyl group can be introduced by Friedel–Crafts acylation with CH_3CH_2COCl/AlCl_3 followed by reduction with H^2/Pd, and a sulfonic acid group can be introduced by sulfonation with SO_3/H_2SO_4.
What is an immediate precursor of the target? The final step will involve introduction of one of three group —chlorine, propyl, or sulfonic acid—so we have to consider three possibilities. Of the three, the chlorination of o-propylbenzenesulfonic acid can’t be used because the reaction would occur at the wrong position. Similarly, a Friedel–Crafts reaction can’t be used as the final step because this reaction doesn’t work on sulfonic acid substituted (strongly deactivated) benzenes. Thus, the immediate precursor of the desired product is probably m-chloropropylbenzene, which can be sulfonated to give a mixture of product isomers that must then be separated.
What is an immediate precursor of m-chloropropylbenzene? Because the two substituents have a meta relationship, the first substituent placed on the ring must be a meta director so that the second substitution will take place at the proper position. Furthermore, because primary alkyl groups such as propyl can’t be introduced directly by Friedel–Crafts alkylation, the precursor of m-chloropropylbenzene is probably m-chloropropiophenone, which could be catalytically reduced
What is an immediate precursor of m-chloropropiophenone? Propio- phenone, which could be chlorinated in the meta position.
What is an immediate precursor of propiophenone? Benzene, which couldundergo Friedel–Crafts acylation with propanoyl chloride and AlCl_3
The final synthesis is a four-step route from benzene: