3.3: Other Aromatic Substitutions
After completing this section, you should be able to
- write a balanced equation for the halogenation (F, Cl, Br, I) of benzene in the presence of a suitable catalyst or promoter.
- draw the resonance contributors for the carbocation which is formed during the reaction of chlorine or bromine with benzene.
- write the equation for the nitration and sulfonation of benzene.
- write the detailed mechanism for the nitration and sulfonation of benzene.
- write the equation for the reduction of an aromatic nitro compound to an amine.
- identify aromatic sulfonation as being a reversible process, and describe the conditions under which the forward and reverse reactions are favoured.
- write the equation for the desulfonation of an aromatic sulfonic acid.
- identify aromatic sulfonic acids as being key intermediates in the manufacture of sulfa drugs.
There are many other kinds of electrophilic aromatic substitutions besides bromination, and all occur by the same general mechanism. Let’s look at some of these other reactions briefly.
Aromatic Halogenation
Aromatic rings react with Cl 2 in the presence of FeCl 3 catalyst to yield chlorobenzenes, just as they react with Br 2 and FeBr 3 . This kind of reaction is used in the synthesis of numerous pharmaceutical agents, including the antiallergy medication loratadine, marketed as Claritin.
Lewis Acidic Catalysts
Halogens need the help and aid of Lewis Acidic Catalysts to activate and become very strong electrophiles as they polarize the Br-Br bond. An A ctivated halogen, X + , where X= Br or Cl, reacts with benzene as it is a much better electrophile than X 2 alone.
Examples of Lewis Acidic Catalysts are Ferric halides (FeX 3 ) and Aluminum Halides (AlX 3 ) where X= Br or Cl. We had covered the activation of the halogens using Ferric halides (FeX 3 ); now, let's observe the activation using Aluminum Halides (AlX3).
In the example of bromine, in order to make bromine electrophillic enough to react with benzene, we use the aid of an aluminum halide such as aluminum bromide.
With aluminum bromide as a Lewis acid, Br 2 reacts with AlBr 3 to form a complex structure for Br + . The presence of this complex for Br + is a much better electrophile than Br 2 alone.
As the bromine has now become more electrophillic after activation of a catalyst, an electrophillic attack by the benzene occurs at the terminal bromine of Br-Br-AlBr 3 . The mechanism continues as presented in the previous section. Since the by-product aluminum tetrabromide is a strong nucleophile, it pulls of a proton from the Hydrogen on the same carbon as bromine. In the end, the catalyst regenartes as it is not consumed during the reaction.
Dissociation Energies of Halogens and its Effect on Halogenation of Benzenes
The electrophillic bromination of benzenes is an exothermic reaction. Considering the exothermic rates of aromatic halogenation decreasing down the periodic table in the Halogen family. Fluoridation is the most exothermic, and Iodination is the least. Being so exothermic, a reaction of flourine with benzene is explosive! For iodine, electrophillic iodination is generally endothermic, hence a reaction is often not possible. Similar to bromide, chlorination would require the aid of an activating presence such as Alumnium Chloride or Ferric Chloride. The mechanism of this reaction is the same as with Bromination of benzene.
Iodine and Fluorine need specific reagents
Iodine and fluorine cannot be introduced into an aromatic ring by the method used for bromine and chlorine. On its own, iodine is unreactive with aromatic rings. Still, one method for aromatic iodination is treatment in the presence of a copper salt such as copper(II)chloride, where I 2 is oxidized to a more powerful electrophilic species that reacts as if it were I + .
In contrast, fluorine is too reactive, so it cannot be used directly for aromatic monofluorination. However, fluorinating agents like 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (also known as F-TEDA-BF 4 ) sold commercially as Sectfluor® offer convenient sources of “F + ” for this type of reaction.
Electrophilic aromatic halogenations also occur in the biosynthesis of many naturally occurring molecules, particularly those produced by marine organisms. In humans, the best-known example occurs in the thyroid gland during the biosynthesis of thyroxine, a hormone involved in regulating growth and metabolism. The amino acid tyrosine is first iodinated by thyroid peroxidase, and two of the iodinated tyrosine molecules then couple. The electrophilic iodinating agent is an I + species, perhaps hypoiodous acid (HIO), that is formed from iodide ion by oxidation with H 2 O 2 .
More than 20% of all pharmaceutical agents sold contain fluorine, including 30% of the top 100 drugs sold. Sitagliptin (Januvia), used to treat type 2 diabetes, fluoxetine (Prozac), an antidepressant, and atorvastatin (Lipitor), a statin used to lower cholesterol, are examples.
Aromatic Nitration
Aromatic rings are nitrated by reaction with a mixture of concentrated nitric and sulfuric acids.
Sulfuric Acid Activation of Nitric Acid
The first step in the nitration of benzene is to activate HNO 3 with sulfuric acid to produce a stronger electrophile, the nitronium ion. The formation of the nitronium ion is through the protonation of nitric acid by sulfuric acid, which causes the loss of a water molecule and formation of a nitronium ion.
Because the nitronium ion is a good electrophile, it is attacked by benzene to produce Nitrobenzene.
Mechanism
(Resonance forms of the intermediate can be seen in the generalized electrophilic aromatic substitution)
Electrophilic nitration of an aromatic ring does not occur in nature but is particularly important in the laboratory because the nitro-substituted product can be reduced by reagents such as iron, tin, or SnCl 2 to yield the corresponding arylamine, ArNH 2 . Attachment of an amino group (–NH 2 ) to an aromatic ring by the two-step nitration/reduction sequence is a key part of the industrial synthesis of many dyes and pharmaceutical agents. We’ll discuss more reactions of aromatic nitrogen compounds in Chapter 10.
Aromatic Sulfonation
Aromatic rings can be sulfonated by reaction with so-called fuming sulfuric acid, a mixture of \(\ce{H2SO4}\) and \(\ce{SO3}\). The reactive electrophile is either \(\ce{HSO3^{+}}\) or neutral \(\ce{SO3}\), depending on reaction conditions, and substitution occurs by the same two-step mechanism seen previously for bromination and nitration (Figure \(\PageIndex{2}\)). Note, however, that the sulfonation reaction is readily reversible. It can occur either forward or backward, depending on the reaction conditions. Sulfonation is favored in strong acid, but desulfonation (benzenesulfonic acid to produce benzene) is favored in hot, dilute aqueous acid.
Mechanism
To produce benzenesulfonic acid from benzene, fuming sulfuric acid and sulfur trioxide are added. Fuming sulfuric acid is a concentrated solution of dissolved sulfur trioxide in sulfuric acid. The sulfur in sulfur trioxide is electrophilic because the oxygens pull electrons away from it because oxygen is very electronegative. The benzene attacks the sulfur (and subsequent proton transfers occur) to produce benzenesulfonic acid.
Reverse Sulfonation
Sulfonation of benzene is a reversible reaction. Sulfur trioxide readily reacts with water to produce sulfuric acid and heat. Therefore, by adding heat to benzenesulfonic acid in diluted aqueous sulfuric acid the reaction is reversed.
Because sulfonation is a reversible reaction, it can also be used in further substitution reactions in the form of a directing blocking group because it can be easily removed. The sulfonic group blocks the carbon from being attacked by other substituents and after the reaction is completed it can be removed by reverse sulfonation.
Aromatic sulfonation does not occur naturally but is widely used in the preparation of detergents, dyes, and pharmaceutical agents. For example, the sulfa drugs, such as sulfanilamide, were among the first clinically useful antibiotics. Although largely replaced today by more effective agents, sulfa drugs are still used in the treatment of meningitis and urinary tract infections. Another example is Bezenesulfonyl Chloride, which is a precursor to sulfonamides, which are used in chemotherapy. These drugs are prepared commercially by a process that involves aromatic sulfonation as its key step.
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Bezenesulfonyl Chloride |
Sulfanilamide |
Feeling Curious? https://en.wikipedia.org/wiki/Sulfanilamide
Exercises
1. What is/are the required reagent(s)for the following reaction:
- Answer
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SO 3 and H 2 SO 4 (fuming)
What is the product of the following reaction:
- Answer
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Why is it important that the nitration of benzene by nitric acid occurs in sulfuric acid?
- Answer
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Sulfuric acid is needed in order for a good electrophile to form. Sulfuric acid protonates nitric acid to form the nitronium ion (water molecule is lost). The nitronium ion is a very good electrophile and is open to attack by benzene. Without sulfuric acid the reaction would not occur.
Write a detailed mechanism for the sulfonation of benzene, including all resonance forms.
- Answer
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Draw an energy diagram for the nitration of benzene. Draw the intermediates, starting materials, and products. Label the transition states.
- Answer
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In each case, how many products would be possible for the bromination of p -xylene, o -xylene, and m -xylene?
- Answer
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If toluene is treated with D 2 SO 4 all the hydrogen’s are replaced with deuterium. Explain.
- Answer
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The deuterium is added to the ring. When the ring “re-aromatizes” the base scavenges the hydrogen before the deuterium and therefore is left on the ring. Continues for the rest of the hydrogen on the ring.
Make certain that you can define, and use in context, the key term below.
- nitronium ion, (NO +2 )
References
- Laali, Kenneth K., and Volkar J. Gettwert. “Electrophilic Nitration of Aromatics in Ionic Liquid Solvents.” The Journal of Organic Chemistry 66 (Dec. 2000): 35-40. American Chemical Society.
- Malhotra, Ripudaman, Subhash C. Narang, and George A. Olah. Nitration: Methods and Mechanisms. New York: VCH Publishers, Inc., 1989.
- Sauls, Thomas W., Walter H. Rueggeberg, and Samuel L. Norwood. “On the Mechanism of Sulfonation of the Aromatic Nucleus and Sulfone Formation.” The Journal of Organic Chemistry 66 (1955): 455-465. American Chemical Society.
- Vollhardt, Peter. Organic Chemistry : Structure and Function. 5th ed. Boston: W. H. Freeman & Company, 2007.