Aromatic electrophilic substitution: a different way of predicting regiospecificity

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Every introductory course or text on aromatic electrophilic substitution contains an explanation along the lines of the resonance diagram shown below. With an o/p directing group such as NH2, it is argued that negative charge accumulates in those positions as a result of the resonance structures shown.

groups1

MEP for PhNH2. Click for 3D.

The opposite occurs for electron withdrawing groups. Shown below is a group such as BR2, a somewhat unusual choice it has to be said (and indeed rather un-represented in the literature as well).

groups2

MEP for PhBH2. Click for 3D.

But stick with me for a little while on this one, since we are now going to pose the question: what the result of combining both groups onto the same aryl ring, as below?

mixed2

MEP for PhBH2NH2. Click for 3D.

The conventional outcome, based on the resonance forms shown in the first two diagrams, is that the two positions annotated with red text are disfavoured, and the two positions labelled with green or orange text are both favoured. Thus far, we are still in “exam question territory”. Reality however intrudes. When a similar combination of electron withdrawing and donating groups is tried out in the lab, only the green outcome is observed, and not the orange. So finally, the point of this blog. Is there any other tool we can use to (correctly) predict the outcome of this particular reaction?

One way of mapping where charge in a molecule accumulates or decreases is a property known as the molecular electrostatic potential (see 10.1021/ja973105j and references cited there for details). Put simply, it measures how attractive (blue) or repulsive (red) any region of the molecule is to a proton placed at any point surrounding the molecule. Mapping these regions produces so-called iso-surfaces, where the measure of repulsion or attraction is the same everywhere on this surface.

So now, if you click on the first diagram, you will see this MEP. Notice how it is blue close to the o or p positions, and does its best to avoid the m position.

Molecular electrostatic potential

Molecular electrostatic potential

Clicking on the second diagram will reveal the opposite.

Molecular electrostatic potential

Molecular electrostatic potential

Thus far this simple picture is in perfect accord with the simple resonance diagrams we started with. But the advantage of this MEP method is that the effects of two (or indeed more) substituents can be properly combined to give an overall effect. Thus in the third diagram, you can now see that the blue accumulates only over the green-text region, and not at all over the orange-text region!

Molecular electrostatic potential

Molecular electrostatic potential

OK, one can derive a resonance structure in 5 seconds in an exam. One can hardly compute a MEP under such conditions. But what this example shows is that sometimes, quantum mechanics produces results which cannot be simply reduced to memorable rules, but must be applied natively to get the correct result.

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