Strategies for Synthesizing Disubstituted Benzenes

We've explored Electrophilic Aromatic Substitution (EAS) reactions and how substituents on the aromatic ring influence both the rate and position of further substitution. Activating groups make the ring more reactive and direct incoming groups to the ortho/para positions, while deactivating groups make the ring less reactive and direct to the meta position. We've also seen how blocking groups can temporarily protect a site, allowing us to perform other reactions. What if our desired substitution pattern isn't directly achievable due to the directing effects of existing groups?

For example, suppose you are tasked with synthesizing, 1-ethyl-3-methylbenzene.

If you attempted to install the ethyl group (Friedel Crafts) and then the methyl group (another Friedel Crafts) you would run into two problems.

  1. Installing an alkyl group (ethyl or methyl) activates the ring, so the second alkylation would over alkylate in both the ortho and meta positions.
  2. The obvious problem is you are not producing the meta substituted dialkylbenzene.

Polarity Reversal (Reactivity Tuning)

One solution to this is called "polarity reversal" or "reactivity tuning".  This relies on the fact that some functional groups can be readily transformed into others. By strategically manipulating these transformations, we can influence the regiochemistry of aromatic substitution.

Carbonyl to Alkyl Transformation

Recall that the products of Friedel Craft acylation, a ketone, can be reduced to form alkyl groups.  So, if we install an acyl group (meta-directing deactivator) via a Friedel Crafts acylation first, the sebsequent Friedel Crafts alkylation should occur in the meta position.  This reversal of polarity solves the two problems.  SInce it is a deactivator of alkylation is not as much of an issue and the methyl group is directed to the meta position.  Reduction of the ketone from the first acylation would result in the desired meta substituted dialkyl benzene. The reduction of aryl ketones with Zn(Hg) amalgamate in HCl is known as the Clemmensen reduction.

Nitro to Amino Transformation

Example: Synthesis of meta-bromoaniline.  Recall that we cannot directly introduce a -NH2 group onto a ring.  We must first nitrate (-NO2) and then reduce to the -NH2.

Wrong Approach 1

If you were to brominate first, the Br is an ortho/para-directing deactivator and would result in the wrong substitution pattern upon nitration.

Wrong Approach 2

Likewise, if you performed the nitration first and then reduced to the amino, you would also result in the wrong substitutuin pattern  upon bromination.  In this case, the polarity reversal was not in our favor.

Correct Solution

In this case simply performing a nitration, followed by bromination and then reduction would lead to the appropriate substitution pattern.

Sulfonyl Blocking

Sulfonyl groups, particularly the sulfonic acid group (-SO3H), serve as valuable blocking groups in electrophilic aromatic substitution (EAS) reactions. Their utility stems from two key properties:

  1. Reversibility: Sulfonation is a reversible reaction. While the introduction of the sulfonic acid group requires harsh conditions (typically concentrated sulfuric acid or fuming sulfuric acid), it can be removed under milder acidic conditions (aqueous acid and heat). This allows chemists to temporarily block a position on the aromatic ring, perform other reactions, and then regenerate the original molecule.

  2. Directing Effects: The sulfonic acid group is a strongly deactivating group and a meta director. This means that it discourages further electrophilic substitution and directs incoming groups to the meta position relative to the sulfonic acid.

Example: Synthesis of ortho-nitrotoluene

Wrong Approach

Since the methyl group of toluene is a ortho/para-directing activator, nitration results in the unwanted para product as the major isomer.

Correct Approach using Sulfonyl Blocking

Sulfonylation of toluene results in the sulfonic acid group be placed in the para position, blocking that position from further reactions.  Subsequent Nitration is then directed to the ortho position.  Removal of the sulfonic acid provides the ortho-nitrotoluene.