15.3: Multiple Substituents and Heteroaromatic Rings

We've described the directing effects when a single functional group is attached to the benzene ring, but what happens when more than one substituent is on a ring? Which one controls the regioselectivity? Well, there are three rules to follow:

1. often the directing effects reinforce each other

2. in cases where the effects are opposite, it is the more activating group that controls the regioselectivity.

3. when two groups are similar in activation, regioselectivity is controlled by sterics, and the substitution will occur at the less sterically hindered site.

Finally, what happens in heteroaromatic rings and polycyclic aromatic hydrocarbons? It turns out that nothing changes, but you will need to draw all of the possibilities and decide based on the resonance structures you draw. Here’s an example:

Here’s another example:

Regioselective synthesis via electrophilic aromatic substitution (S_EAr) involves a good degree of planning. Attention needs to be paid to the order of addition. Consider the retrosynthesis below.

We know that we need to add an acyl group and a bromo group, but which one do we add first?

A bromo substituent is ortho-/para-directing, but the acyl group is meta-directing. In the structure, the groups are meta, so you would need to add the acyl group first.

Here’s another example:

The two caveats in multistep synthesis are that an aromatic ring more deactivated than monohalogens will not react, and that any group more than or equal in activation than -NH₂ will substitute more than once.