Synthesis of Trisubstituted Benzenes

One ol the surest ways to learn organic chemistry is to work synthesis problems. The ability to plan a successful multistcp synthesis of a complex molecule requires a working knowledge of tlie uses and limitations of a great many organic reactions. Not only must you know which reactions to use, you tnust also knoiv 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 valuable in the synthesis of substituted arc unatic 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 an excellent way to gain confidence using the many reactions learned in tlie past few chapters. 

Strategy Draw the target molecule, identify the substituents, and recall how each group can be introduced separately. Then plan retrosynthetically. 

This ring will give a mixture of isomers on bromination. 

This deactivated ring will not undergo a Friedel-Crafts reactior 

Problem 16.21 How would you prepare diphenylmethane, (Ph)2CH2, from benzene and an appropriate acid chloride  

CHAPTER 16 I Chemistry of Benzene Electrophilic Aromatic Substitution 

During the previous discussion of strategies for working synthesis problems in Section 8.10, we said that it s usually best to work a problem retro-syntheticallyj or backward. 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. 

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Oxidation of Aromatic Compounds Reduction of Aromatic Compounds Synthesis of Trisubstituted Benzenes... 

The development of synthetic methods for solving the problem of the synthesis of substituted arenes by Friedel-Crafts substitution has focused on three-component coupling of acetylenes. However, there are certain restrictions since attempts at trimerizing two or three different alkynes led to complex mixtures (Scheme 2.3) [9]. Synthesis of trisubstituted benzenes is also problematic in terms of the lack of selectivity during the initial formation of metallocycle as well as the reaction with the third alkyne [9]. 

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