When it comes to the benzyne pathway, there's one more thing we need to learn about because so far, all I showed you was benzene by itself. But what happens if that benzyne is asymmetrical and has substituents on it? How do we know which side of the benzyne is going to get attacked? It turns out that this is what we call benzyne regioselectivity and there's actually a trend for it. Let's learn it.
Here's the issue. Let's say that we have the following benzyne intermediate and I'm at the point where my NH3 is going to attack. Well, notice that now I've added an OH group. If my NH3 attacks from here, I would get a lone pair forming here and eventually, I'm going to get the NH2 close to the OH. Or if my NH3 attacks here, I'm going to get the lone pair forming here and eventually my NH3 will be meta to the OH. Which one is right? Do I just get a combination of products? Actually, no. The identity of the location of where it adds is based on the type of group that is next to the benzyne.
I'm going to explain the theory. But thankfully, memorizing is really easy because this follows the same trends that we've seen all throughout benzene chemistry, which is that a donating group is going to favor the ortho position and a withdrawing group is going to favor the meta position. We remember how withdrawing groups are always meta directors and donating groups are ortho/para directors. It's the same thing here except we're not going to worry about para because para doesn't even have a benzyne on it. I'm just worried about ortho and meta.
Here's the theory behind it. Notice that what I have here for OH is actually a donating group. If I have a donating group, that would put me into the bottom category here. When I have to form that negative charge, I have 2 different options. I could either form the negative charge here close to the donating group or I could form the negative intermediate lower away from it. Which one do you think is going to be more stable, having it closer to the donating or further? What's going to happen is that the NH3 is going to selectively pick the ortho position just so that it can put the negative charge further away from the donating group. That's why when you have an electron-donating group, ortho substitution is going to predominate.
The opposite is true of a withdrawing group. If I have a strong withdrawing group, then we want the negative charge to be as close to it as possible. Then that's going to favor meta substitution. You guys can totally know the theory but you can also just memorize it and that would be fine. Let's go ahead and do a practice problem. I noticed this is going to be a kind of multi-step synthesis, a lot going on, a few other reagents. Try to do your best. Notice that here, you do have to worry about regiochemistry. Try to pick the right answer and then I'll go ahead and I'll give you the right answer.