15.1: Electrophilic Aromatic Substitution

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Jan 4, 2023
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- 15: Aromatic Substitution
- 15.2: Regioselectivity in Electrophilic Aromatic Substitution

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Since the $π$ electrons in an aromatic ring are lower in energy than a simple alkene, one must overcome the aromatic stabilization energy for reaction with an electrophile to occur. Thus, one needs a very strong electrophile (one that normally has a full positive charge and thus a very, very low LUMO). Alternatively, one could add a substituent group that increases the nucleophilicity of the benzene ring, raising the HOMO. Let’s do the first case – reaction between a benzene ring and a strong generic electrophile, E⁺.

Screen Shot 2022-12-29 at 12.33.52 PM.png

What kinds of electrophiles are used here?

1. halogenation – X⁺ (X^$δ$⁺ does not work, ie. Br₂ does not work by itself)

must add a Lewis acid:

Screen Shot 2022-12-29 at 12.34.04 PM.png

2. nitration – NO₂⁺ (nitronium ion); normally use HNO₃/H₂SO₄, but there are also stable salts that are rarely used (NO₂BF₄, NO₂PF₆).

Screen Shot 2022-12-29 at 12.34.13 PM.png

3. sulfonylation – SO₃H⁺ (sulfonium ion); use H₂SO₄/SO₃ (fuming sulfuric acid)

Screen Shot 2022-12-29 at 12.34.20 PM.png

4. Friedel-Crafts acylation - (acylium ion)

a. intermolecular processes: use Lewis acid and either acid chloride or anhydride.

Screen Shot 2022-12-29 at 12.34.33 PM.png

b. intramolecular processes: use a protic acid or a Lewis acid

Screen Shot 2022-12-29 at 12.34.49 PM.png

Now, so far, if we had to describe the types of groups we are adding to the benzene ring, we would say they all are deactivating. These groups are all electron-withdrawing and pull electron density from the ring, lowering its reactivity even further (lowers both HOMO and LUMO). This makes the product less nucleophilic than the starting material. Can we rank these substituents in terms of ability to deactivate (or most electron-withdrawing ability)?

Screen Shot 2022-12-29 at 12.34.54 PM.png

But what if we wanted to add an electron-donating group to the benzene ring?

5. Friedel-Crafts alkylation – R⁺ (2^o or 3^o carbocation)

a. use alkyl halide + AlCl₃

Screen Shot 2022-12-29 at 12.35.05 PM.png

This reaction is very difficult to stop at monosubstitution because the initial product mixture is not more nucleophilic than the starting material (tBu is electron-donating, and thus activating to the benzene ring). One pitfall of this reaction is that some carbocations are subject to rearrangement. For example:

Screen Shot 2022-12-29 at 12.35.15 PM.png

How does this occur? The major pathway proceeds through rearrangement to a secondary carbocation. Thus, better ways have been developed to add a 1^o alkyl chain onto a benzene ring.

Screen Shot 2022-12-29 at 12.35.27 PM.png

b. use alcohol + protic acid

Screen Shot 2022-12-29 at 12.35.39 PM.png

So, now we can include alkyl groups in our reactivity series:

Screen Shot 2022-12-29 at 12.35.45 PM.png

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