[wilson]

Hi all:
We know that in Electrophilic Aromatic Substitution, the 1st substituent will have either a activating/deactivating, o/m/p effect on the 2nd substituent. Then what effect will the 2nd substituent have on the 3rd? Is it a straight foward and clearcut, or do we have to work out on stability of intermediates,  and the nature of the electrophile and nucleophile and the aryl (ring)?

[movies]

That's all going to depend on the nature of the substituents.  Two EWGs will behave differently than two EDGs, or a combination of the two.

Think about some of these possibilities and try to rationalize what might happen.

I think it is helpful to pick a molecule with three substituents and try to figure out how to make it.  Try 3-bromo-4-amino-anisole, for example.

(In case you don't know, anisole is methoxybenzene).

[wilson]

That's all going to depend on the nature of the substituents.  Two EWGs will behave differently than two EDGs, or a combination of the two.

Think about some of these possibilities and try to rationalize what might happen.

I think it is helpful to pick a molecule with three substituents and try to figure out how to make it.  Try 3-bromo-4-amino-anisole, for example.

(In case you don't know, anisole is methoxybenzene).

Here's my try:
1. Substitute methoxy on benzene using EAS to yield anisole
2. Substitute amine on anisole using EAS to yield para-aminoanisole
3. Substitute bromine on an ortho position on para-aminoanisole to get 3-bromo-4-amino-anisole
The intermediate arenoniuum ion can be stabilized by delocalizing the positive charge onto the amine group which is an EDG.

I do not know what reactants/catalysts to use for the 1st two steps though.
Sodium methoxide and ammonia?

[AhmedEzatAlzawalaty]

activating groups together have a net action of activating the ring.
deactivating groups are the same.activating and deactivating groups have the net action of activation i mean the activating groups predominate

[movies]

Here's my try:
1. Substitute methoxy on benzene using EAS to yield anisole
2. Substitute amine on anisole using EAS to yield para-aminoanisole
3. Substitute bromine on an ortho position on para-aminoanisole to get 3-bromo-4-amino-anisole
The intermediate arenoniuum ion can be stabilized by delocalizing the positive charge onto the amine group which is an EDG.

I do not know what reactants/catalysts to use for the 1st two steps though.
Sodium methoxide and ammonia?

Those first two step would be a problem because there aren't many good electrophilic O or N groups.  Suppose you just start from phenol or anisole.  (By the way, you can introduce oxygen via a Sandmeyer reaction, but it's steppy.)

Think about the third step you proposed.  If you have 4-aminoanisole (it's actually called para-anisidine) and you tried to use EAS to add Br, do you think you would get exclusively substitution ortho to the NH₂?  What would happen if you changed the nature of the nitrogen substituent?

[wilson]

Maybe I should have been clearer.
For the first step, what’s the need for introducing oxygen? OCH3 can be easily substituted on benzene, I thought.
Then, the methoxy group acts as an ortho/para directing group, for the substitution of the amine group in the second step. We shall separate para-anisidine.
Because the ring is now electron rich, surely we can brominate para-anisidine to get 3-bromo-4-amino-anisole.
We will also get 2-bromo-4-amino-anisole, because of the influence of the methoxy group, but that’s just a side reaction?

I am not too sure on how changing the nature of the nitrogen substituent will help.

Perhaps you can share your proposal?

[movies]

What way do you know to introduce an O through EAS?

Also what N reagent do you propose?

[wilson]

I meant that the methoxy can be substituted directly onto benzene.

[movies]

That's kinda hard to do.  What way do you know to do that?