16.10 • Synthesis of Polysubstituted Benzenes
As discussed in the Introduction to Organic Synthesis in Section 9.9, one of the surest ways to learn organic chemistry is to work synthesis problems. The ability to plan a successful multistep synthesis of a complex molecule requires a working knowledge of the uses and limitations of a great many organic reactions. Not only must you know which reactions to use, you must also know when to use them because the order in which reactions are carried out is often critical to the success of the overall scheme.
The ability to plan a sequence of reactions in the right order is particularly important in the synthesis of substituted aromatic rings, where the introduction of a new substituent is strongly affected by the directing effects of other substituents. Planning syntheses of substituted aromatic compounds is therefore a good way to gain confidence in using the many reactions discussed in the past few chapters.
As we said in Section 9.9, it’s usually best to work a synthesis problem backward, or retrosynthetically. Look at the target molecule and ask yourself, “What is an immediate precursor of this compound?” Choose a likely answer and continue working backward, one step at a time, until you arrive at a simple starting material. Let’s try some examples.
Synthesizing a Polysubstituted Benzene
How would you synthesize 4-bromo-2-nitrotoluene from benzene?
StrategyDraw 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 Br2/FeBr3, a methyl group can be introduced by Friedel–Crafts alkylation with CH3Cl/AlCl3, and a nitro group can be introduced by nitration with HNO3/H2SO4.
SolutionAsk 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 dominate the deactivating nitro group and direct bromination to the correct 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 mixture of products 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.
Synthesizing a Polysubstituted Benzene
Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.
StrategyDraw 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 Cl2/FeCl3, a propyl group can be introduced by Friedel–Crafts acylation with CH3CH2COCl/AlCl3 followed by reduction with H2/Pd, and a sulfonic acid group can be introduced by sulfonation with SO3/H2SO4.
Solution“What is an immediate precursor of the target?” The final step will involve introduction of one of three groups—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?” Propiophenone, which could be chlorinated in the meta position.
“What is an immediate precursor of propiophenone?” Benzene, which could undergo Friedel–Crafts acylation with propanoyl chloride and AlCl3.
The final synthesis is a four-step route from benzene:
Planning an organic synthesis has been compared with playing chess. There are no tricks; all that’s required is a knowledge of the allowable moves (the organic reactions) and the discipline to plan ahead, carefully evaluating the consequences of each move. Practicing may not be easy, but it’s a great way to learn organic chemistry.