Making Polysubstituted Benzenes

Since the position of electrophilic attack on a substituted benzene ring is controlled by the substitutent already present rather than the approaching electrophile, the order of events in the synthesis of polysubstituted benzenes need careful planning to ensure success.

The two factors that need to be monitored are:

• regiochemistry
• reactivity (for example Friedel-Crafts reactions are limited to halobenzenes and activated benzenes)

(STUDY TIP : students often get this concept of what component is in control confused.
 Try thinking about it in terms of an aircraft (the E⁺ ) coming into land at an airport ( the Ar-X )... it is the control tower at the airport on the ground (-X) that does the "directing" of which runway and which ramp the aircraft should go to)
 

• Draw the target product and label the substituents with their directing effects
• Look at these directing effects to see which (if any !) align to allow the introduction of the appropriate group
• If there is a choice, introduce the more activating group first... it will make the subsequent reactions easier
• Remember that some functional groups can undergo reactions that change their directing effects
• Check the order of reactions for compatibility

	Here the nitro group could direct the bromine to the correct position  Therefore in planning the synthesis we should use the nitro group to introduce the bromine
Actual synthesis:
What would the product be if the order of the steps in the synthesis were reversed ?

	Here neither group directs to the correct location of the other.  But since the carboxylate could be introduced by the oxidation of a methyl group, which directs o,p- we can use the methyl to direct the nitro group to the correct position.
Actual synthesis:
Note that the oxidation has to be after the nitration to get the correct orientation and that the Friedel-Crafts alkylation has to be before the nitration since nitrobenzene is too deactivated to undergo alkylation.