Electrophilic Aromatic Substitution: From a Biological Standpoint

          In an electrophilic aromatic substitution reaction, an electrophile attacks the aromatic ring and replaces one of the hydrogen atoms.  All reactions occur via a two-step mechanism, regardless of the electrophile.  The first step a carbocation is formed by the addition of the electrophile.  In the second step, the aromatic ring is re-formed when there is a loss of a proton.  The general mechanism is shown in Figure 1 (1). 

     



                              Figure 1

Five examples of electrophilic aromatic substitutions is shown in Figure 2 (1).
 

                   Figure 2


A substituent group affects the electrophilic aromatic substitution in two ways: the rate of the reaction and the orientation.  If a substituent activates a benzene ring, such as an alkyl group, then substitution is directed ortho and para.  If a substituent deactivates a benzene ring, such as a nitro group, then substitution is directed meta (1).     

The purpose of this blog post was to research and find out how electrophilic aromatic substitutions are used in a biological sense.  After searching the internet, it was quickly noted that many of these reactions take place in enzyme pathways.  However, they are also used in synthesis of many different drugs. 

An example of a drug synthesized using electrophilic aromatic substitution is 2-(4-isobutylphenyl)propanoic acid, most commonly known as ibuprofen (2).  Isobutylbenzene first undergoes a Friedel-Crafts acylation to produce a ketone.  The alkyl group directs the substitution to ortho and para positions; para dominates because of the size of the electrophile.  This ketone is then reduced using borohydride, which creates an alcohol.  Nucleophilic substitution then takes place using HBr, replacing the OH group with Br.  This product then reacts with NaCN in a nucleophilic substitution reaction to replace the Br with CN.  Finally, an acid-cataylized reaction using sulfuric acid hydrolyzes the nitrile group to a carboxylic acid.  Thus the final product of ibuprofen is formed.  The mechanism of this synthesis is shown in Figure 3 (3).

   















                                Figure 3


In conclusion, electrophilic aromatic substitutions are common in laboratory synthesis and within biological pathways.  They have a profound impact within everyday use, even though one might not realize it.  In the synthesis of ibuprofen, the very first step is an electrophilic aromatic substitution.  These reactions are important because they produce products that can then undergo other substitutions that will yield the desired compound.  As technology advances scientists will be able to learn even more knowledge about these type of reactions, specifically in these two areas.               

References

1) Smith, J. Organic Chemistry, 3rd ed.; McGraw-Hill: New York, 2011.

2) Sigma Aldrich. Ibuprofen. http://www.sigmaaldrich.com/catalog/product/sigma/i4883?lang=en&  
 region=US (accessed Mar 12, 2014)

3) Dewick P. Essentials of Organic Chemistry: For Students of Pharmacy, Medicinal Chemistry and Biological Chemistry. John Wiley & Sons Ltd: West Sussex, 2006