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Chemistry 2131:
Organic Chemistry for the Life Sciences(3)

Electrophilic Aromatic Substitution Reactions

• one of the hallmarks of aromatic molecules is that despite a high degree of unsaturation, they are resistant to electrophilic addition reactions. The characteristic reactions of aromatic compounds are the electrophilic aromatic substitution reactions. An important difference between these two reaction types is that in the former the pi bond is lost and replaced by two sigma bonds, and in the latter there is no net loss of pi electrons.
• these reactions are very similar and are in many ways reminiscent of electrophilic addition reactions. The major differences are that the electrophile involved must be a very strong electrophile (very electron deficient) and that the aromatic ring must be regenerated in the final step of the reaction.
• the first step in the reaction is the generation of a strong electrophile. This is the step that will differ between reactions.
• in the second step, a pair of electrons from the pi cloud attack the electrophile breaking the aromaticity of the ring and generating a carbocation intermediate. It is very important to note that this carbocation is resonance stabilized by the remaining 4 electrons of the pi cloud.
• in the final step of the reaction a strong base abstracts a proton from the carbon atom that received the electrophile to regenerate the aromatic ring.
• energetically speaking, the transition state corresponds to the attack on the electrophile, there is a slight trough where the resonance stabilized carbocation intermediate resides, another transition state as the proton is abstracted and finally a plateau corresponding to the final product.
• we will look at a number of reactions is detail.

2. Halogenation:

• we know that the alkenes and alkynes react spontaneously with bromine or chlorine in solvents such as CCl₄, this is the halogenation reaction we have already seen. Aromatics need much harsher conditions. Generally the reaction must take place in liquid bromine or chlorine, no solvent, and a Lewis acid catalyst. In case you have forgotten from chem I and II, a Lewis acid is defined as a species that can form a new covalent bond by accepting a pair of electrons.
• the first step in the bromination reaction is the formation of a complex between Br₂ and the Lewis acid catalyst FeBr₃. A lone pair on bromine attacks the electron deficient iron atom togive a complex where the iron atom is negatively charged and the closest Br is positively charged. The complex behaves like Br+ and Fe-Br₄.
• so we have generated a strong electrophile. The next step is that attack of a pair of electrons from the pi cloud to give a carbocation intermediate and Fe-Br₄. It is important to realize that the positive charge is shared over 3 carbon atoms and is thus resonance stabilized.
• to regenerate the aromatic ring one of the Br atoms from the complex removes the proton from the carbon that received the original Br, and the electrons from the C-H bond regenerate the aromatic sextet.

3. Nitration:

• let's look at the next reaction, nitration. The net result of this reaction will be the addition of a nitro group, -NO₂.
• the reaction takes place in concentrated nitric acid (HNO₃) in the presence of sulfuric acid. The first step is the generation of a suitable electrophile. In this case, the electrophile is +NO₂, the nitronium ion. First one must start with a suitable Lewis structure for nitric acid. This involves a nitrogen atom bearing a positive charge doubly bonded to one oxygen atom and singly bonded to two others. One of these is protonated, the other bears a negative charge.
• a lone pair form the OH oxygen atom removes a proton from the sulfuric acid to give a positively charged oxygen. One of the lone pairs on the negatively charged oxygen atom come down to form a pi bond and the H₂O group leaves as water, giving us the nitronium ion.
• the positively charged nitrogen atom is attacked by an electron pair from the pi cloud to give the carbocation intermediate
• One should not here that either of the oxygens can accept a lone pair giving further resonance stabilization
• the aromatic ring is regenerated when HSO₄ removes the proton
• the product is called nitrobenzene.

4. Sulfonation:

• a very similar reaction is the sulfonation reaction which results in the addition of a sulfonyl group (-SO₃H) to give benzenesulfonic acid
• here the potent electrophile is sulfur trioxide (+SO₃H) which is found in hot fuming sulfuric acid. A lone pair from one of the OH group becomes protonated, then leaves generating the above ion and water.
• the reaction proceeds as per usual with attack by a pair of electrons from the pi cloud, resonance stabilization of the carbocation intermediate, then regeneration of the aromatic ring when HSO₄- removes a proton.
• the sulfonyl group is in equilibrium withe the sulfuric acid and can be protonated or not.
• unlike most of these reactions, this reaction is reversible. If the product is heated in steam the reverse reaction takes place.

5. Friedel-Crafts Acylation:

• an acylation reaction is one in which an acyl group is added to another molecule. An acyl group has a carbonyl carbon at the point of attachment and a number of other carbon atoms forming some kind of chain.
• typically, the acyl group comes from an acyl chloride which is the chloride derivative of a carboxylic acid. As we will see later in the course, this group of carboxylic acid derivatives is very reactive.
• to generate the electrophile the acyl chloride is mixed with the Lewis acid AlCl₃. the electrons of the carbon-chloride bond of the acyl chloride attack the electron deficient aluminum atom of the catalyst to give a molecular complex where the Cl is positively charged and the Al is negatively charged. This actually dissociates to give AlCl₄- and the acylium ion. The acylium ion can be resonance stabilized by a lone pair from oxygen giving a carbon oxygen triple bond and a positive charge on the oxygen. One can also use FeCl₃ or ZnCl₂ to generate the acylium ion.
• the rest of the reaction is exactly like all of the others. In the final step, removal of the ring proton to regenerate the aromatic ring, the Cl- from the AlCl₄- acts as base and generated HCl.
• to note, the ketone that is generated can interact with the Lewis acid catalyst to form an inactive complex, so one must add extra catalyst to compensate. The catalyst can be removed from the ketone oxygen by pouring the reaction product in water
• also of note, is that one can get intramolecular acylation reactions. Have a look at this with 4-phenylbutanoyl chloride in AlCl₃.

6. Friedel-Crafts Alkylation:

• this reaction is similar to the acylation reaction above, but results in the addition of an alkyl group rather than an acyl group.
• these can be a little tricky because of rearrangements that occur.
• for a simple example we will use 2-chlorobutane as a starting reagent. The alkyl group is derived from an alkyl halide.
• to generate the strong electrophile, the alkyl halide is reacted with the Lewis acid catalyst AlCl₃. A lone pair from the alkyl halide chloride attacks the electron deficient Al atom to generate a complex.
• if the alkyl halide is secondary or tertiary, the complex can further react to form a carbocation and AlCl₄-. In either case (dissociated or not) the complex or the carbocation can serve as the electrophile.
• the rest of the reaction proceeds as usual, the electrophile is attacked by a pair of electrons from the pi cloud giving a resonance stabilized carbocation intermediate. The ring proton is abstracted by a Cl from AlCl₄- generating HCl and regenerating the catalyst.
• there are several limitiations and complexities of this reaction to be aware of.
• there can be rearrangement of carbocation alkyl groups. This results in a mixture of unexpected products. For example, when primary halides are used (such as 1-chlorobutane) the products are mixed. For this example, one gets a mixture of butylbenzene and sec-butylbenzene in a ratio of 1:2.
• how did this happen? When the primary halide reacted with the Lewis acid catalyst, a complex formed that can rearrange by a hydride shift. This can be attacked instead of the primary complex. Since the secondary carbocation is more stable, it gives the major product.
• this kind of problem can be avoided by using secondary or tertiary alkyl halides to start (i.e. it is not prone to rearrangement)
• another complication of the reaction is that the products of the reaction are more reactive than the benzene stareting product (we'll get to why that should be so soon!). So the products can be multiply alkylated. You can get around this by using a vast excess of benzene.
• another source of alkyl groups for Friedel-Crafts alkylations is the alkenes. In the presence of acids such as sulfuric acid, a carbocation electrophile can be generated (by electrophilic addition) that can be attacked in the usual fashion.