Question 9.4: Synthesize 4-bromo-2-nitrotoluene from benzene.
Synthesizing a Polysubstituted Benzene
Synthesize 4-bromo-2-nitrotoluene from benzene.
S t r a t e g y
Draw the target molecule, identify the substituents, and recall how each group can be introduced separately. Then plan retrosynthetically.
The three substituents on the ring are a bromine, a methyl group, and a nitro group. A bromine can be introduced by bromination with {Br_2}/{FeBr_3}, a methyl group can be introduced by Friedel–Crafts alkylation with {CH_3}{CL}/{AlCl_3}, and a nitro group can be introduced by nitration with HNO_3/H_2SO_4.
Ask yourself, “What is an immediate precursor of the target?” The final step will involve introduction of one of three groups—bromine, methyl, or nitro— so we have to consider three possibilities. Of the three, the bromination of o-nitrotoluene could be used because the activating methyl group would dom- inate the deactivating nitro group and direct bromination to the right position. Unfortunately, a mixture of product isomers would be formed. A Friedel– Crafts reaction can’t be used as the final step because this reaction doesn’t work on a nitro-substituted (strongly deactivated) benzene. The best precursor of the desired product is probably p-bromotoluene, which can be nitrated ortho to the activating methyl group to give a single product.
Next ask, “What is an immediate precursor of p-bromotoluene?” Perhaps toluene is an immediate precursor because the methyl group would direct bromination to the ortho and para positions. Alternatively, bromobenzene might be an immediate precursor because we could carry out a Friedel–Crafts methylation and obtain a mixture of ortho and para products. Both answers are satisfactory, although both would also lead unavoidably to a product mixture that would have to be separated.
“What is an immediate precursor of toluene?” Benzene, which could be methylated in a Friedel–Crafts reaction. Alternatively, “What is an immediate precursor of bromobenzene?” Benzene, which could be brominated.
The retrosynthetic analysis has provided two valid routes from benzene to 4-bromo-2-nitrotoluene.
