Electrophilic Aromatic Substitution

General idea:

            Pi electrons in aromatic rings are much less reactive and delocalize less often than pi electrons isolated in alkenes. These rings can undergo electrophilic reactions with a powerful electrophile. On the other hand, electrophilic addition to aromatic ring is not generally observed because the product is not aromatic.  This can be shown below in figure one.

Figure 1: General aromatic substitution reaction compared to aromatic addition. 

            

            In most cases aromatic rings will undergo electrophilic substitution. This yields a product that is aromatic. In the starting point of a electrophilic aromatic substitution reaction, the energy is low due to the aromaticity. The activation energy for the first step is high. This is where the aromaticity is temporarily lost due to the carbocation intermediate. This is shown in figure two.

Figure 2: Activation energy of substitution in aromatic ring compared to normal alkene. 

            

            There are two basic characteristics found in electrophilic aromatic substitution reactions. 

1.     The electrophilic partner needs to be highly reactive. This increases the energy of the starting material and helps to decrease the activation energy. The electrophile is usually a carbocation.

2.     Another common characteristic in all these reactions is that the aromatic substrate is often activated by the presence of electron-donating heteroatom-containing substituents. The heteroatom is usually nitrogen or oxygen. These stabilize the positive charge on the intermediate, which according to Hammond’s postulate lowers the energy of the transition state and the activation energy. These concepts can be seen in figures 3 and 4.

Figure 3: Example of a highly reactive partner 

Figure 4: Activation energies of inactive substrate compared to an active substrate. 

* Figures 1-4 come from University of California, Davis (chemwiki.ucdavis.edu) 

Biological Example:

            Ergot alkaloid is a compound found in the biosynthetic pathway of fungi.

Ergot means fungi

Alkaloid refers to a family of amine-containing biomolecules.

The alkaloid compounds in fungi have a potent hallucinogenic effect when ingested by humans. This has been seen in history. One famous case was the Salem witchcraft trails. Young women were accused of being witches because of their reactions to the hallucinogenic effect of this fungi (Claviceps purpurea) that contaminated their grains. This can be seen in figure 5 below

Figure 5: Ergot on rye 

botany.hawaii.edu

            An important note in fungal alkaloid biosynthesis involves the aromatic side of the chain. The electrophile (intermediate a) is an allylic carbocation and that intermediate b is stabilized by resonance with ring nitrogen on tryptophan (1). This is shown below in figure 6. 

Figure 6: Fungal alkaloid biosynthesis  

chemwiki.ucdavis.edu

Most ergot alkaloids have a tetracyclic ergoline ring system in their basic structure, shown in figure 7. 

Figure 8 shows a real world example of electrophilic aromatic substitution with DMAT formation (2). 

Figure 8: Reaction mechanism for synthesis of DMAT 

chemistry.mdma.ch/hiveboard/palladium.pdf

References

1. Section 15.5: Electrophilic aromatic substitution reactions.   

http://chemwiki.ucdavis.edu/Organic_Chemistry/ (accessed February 22, 2014).  

2. Ergot on Rye. Botany.hawaii.edu

3. Keller, U.  Biosynthesis of Ergot Alkaloids

                   http://chemistry.mdma.ch/hiveboard/palladium/pdf/Ergot%20-  

                   %20The%20Genus%20Claviceps%20(1999)/TF3168ch5.pdf (accessed February 22, 2014).