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The Sulfonyl Blocking-Group Strategy For Synthesis of Aromatic Molecules

Or, how to just get the “ortho” product without any para- .

Table of Contents

1. Why do para products tend to be favored over听辞谤迟丑辞-听辫谤辞诲耻肠迟蝉?听
2. How Do You Get Just The听辞谤迟丑辞-听Product?
3. The Sulfonyl “Blocking Group” Strategy
4. The Sulfonyl Blocking Group Strategy In Action
5. Combining Sulfonyl Blocking Groups With Polarity Reversal
6. Two Practice Problems
7. Summary: Sulfonyl Blocking Groups
8. Notes

1. I Just Want The ORTHO-听Product, Thank You

Question: Just how selective are听ortho-听para, directors for the ortho- and听para-听products, respectively?

There are two听ortho positions and one听para. All else being equal, we’d expect a ratio of about 2:1 favoring the听ortho.

Is that what we get? No.

In reality, most electrophilic aromatic substitutions give a ratio of products slightly favoring听para听over听ortho. A 60:40 ratio is typical.

Why the preference for para?

Steric effects, mostly. The听辞谤迟丑辞-听positions are adjacent to the substituent, which can block the path of the electrophile. The听para-听position is therefore more accessible for the electrophile to attack.

This 60:40 ratio is just a rough number, and depends on the particular substituent. To really drive products to the听para-, use a听听really bulky group like听t-butyl. This gives听para products almost exclusively.

2. How Do You Get Just The ortho-听Product?

This preference for the听para– product can be annoying. What if we just want the听ortho– product?

Sorry, not an option.听 At least: not yet.听 There aren’t any reactions we’ve learned that are selective for the听ortho– product. So getting to the听辞谤迟丑辞-听in one step, without ever having to separate it from the听para-, just isn’t possible with the knowledge we have.

But, as often happens in organic chemistry, there IS a听work-around. Here it is.

What if we take advantage of the natural preference for听para-听substitution, and install听a group that can be reversibly added to an aromatic ring? This听blocks the para position, which means that any subsequent reaction must go onto the听ortho position.

Then we remove the blocking group, and听voila! we have our听辞谤迟丑辞-听substituted product exclusively.

3. The Sulfonyl “Blocking Group” Strategy

Have we seen any substituents that can be installed reversibly on benzene?

Yes. There are two: sulfonyl (SO₃H) and听t-butyl.

Here, we’ll mostly cover听sulfonyl. (If you just can’t get enough of this topic – completely understandable! –听 I’ll cover听t-butyl in the endnotes.)

Let’s review sulfonation:

• In the forward direction, treating an aromatic ring with heat, SO₃ and acid, puts SO₃H on the ring. [Note 1]
• To remove SO₃H, we just heat the aromatic ring with strong acid (e.g. H₂SO₄), which eventually loses gaseous SO₃.

Here,. the aromatic ring is protonated at the carbon bearing the SO₃H. [Note 2] In the re-aromatization event, SO₃ is lost instead of H+. Once gaseous SO₃ boils off, it’s not coming back.

4. Using SO₃H As A Blocking Group

Let’s show a simple example of this blocking group strategy in action, beginning with methoxybenzene (“anisole”) toward the goal of synthesizing听ortho-bromoanisole.

• Step 1 is to install the SO₃H with SO₃ and strong acid, which will go (mostly) to the para position.
• Step 2 is to install the desired substituent (bromine) on the听ortho position.
• Step 3 is to remove SO₃H with strong acid and heat, giving us our听辞谤迟丑辞-听substituted product.

And there we go. After removal of the sulfonyl, we’re left with only听ortho-bromoanisole.

Hooray!

5. Combining Blocking Sulfonyl Groups With “Polarity Reversal”

We can combine this blocking group strategy with the “polarity reversal”听 and “order of operations” strategies we learned earlier.

For example: how could we use this to make听o-methyl aniline (aka听o-toluidine)?

• We saw that we can’t form C-NH₂ bonds directly through electrophilic aromatic substitution,听 but we can form C-NO₂ and reduce to the NH₂.听 This means we need to install NO₂ on the ortho position.
• This results in the following order of operations: 1) sulfonylation, 2) nitration, 3) removal of SO₃H using strong acid and heat, and 4) reduction of NO₂ to NH_2听using a reductant like zinc and acid (Zn/HCl).
• (it’s probably best to leave the reduction until the end; NH₂, being basic, will interfere with the de-blocking step)

While this is one way to do it, it’s not the only way.听听There’s always an element of choose-your-own-adventure in synthesis.

6. Two Practice Problems

Why not try some of your own? Here’s a few examples to practice with using this strategy:

7. Summary: Sulfonyl Blocking Groups

When you need the听ortho- and only the听ortho-, a blocking group strategy like this one is a useful trick to have in your toolbox.

Having covered some synthetic strategies, it’s likely worth our time to devote a whole post just to worked examples. That will come next!

Notes

Note 1.听This will not occur with 100% selectivity for the para position; there will be some听辞谤迟丑辞-听product as well, and it will need to be separated out at some point. So in one sense we are just switching the step at which we have to separate out the undesired product.

Note 2.听In contrast to ortho-, meta-, or para-, the carbon attached to the substituent is referred to as the ipso– carbon.

t-Butyl As A Blocking Group

To be brutally frank, the sulfonyl strategy doesn’t get a ton of use in modern organic chemistry. One of the problems is that the resulting sulfonic acid groups are quite polar, and this can present its share of problems with isolation and purification. Ask anyone who’s done ion-exchange chromatography about how much they like concentrating their aqueous fractions.听 Yeah, no.听

A different tack is to employ听t-butyl groups as blocking groups. The听t-butyl groups are nice and greasy – perfect for flash chromatography.

First, let’s review. How are听t-butyl groups installed and removed again?

Installation is听via Friedel-Crafts alkylation. We can use either t-BuCl with AlCl₃ or 2-methylpropene with strong acid.

Removal of the听t-butyl group is achieved by heating with an excess of aluminum chloride (AlCl₃) using benzene as solvent. (This also happens to remove the methyl group from anisole as well). These are not exactly mild conditions, which limits the scope of the reaction somewhat听 a lot, but… onward.

t-Butyl as a Blocking Group: In Action

Here’s an example of this blocking group being used toward the synthesis of a听2-hydroxy benzophenone derivative. Starting with anisole (methoxybenzene), the听t-butyl group is added to the听para position. Next, a Friedel-Crafts acylation results in exclusive formation of the ortho– product. Finally, removal of the听t-butyl with AlCl₃ and benzene results in the final product.

Notice that this also pops off the methyl ether – not an easy thing to do! Mild, these conditions are not.

So how does the听removal of the t-butyl group happen?

The reaction probably begins by protonating the ring with trace acid (e.g. HCl) present either in AlCl₃ or from reaction of AlCl₃ with trace water. Protonation of the ring at the para position can then set up re-aromatization听not by loss of H+, but by loss of the t-butyl cation. The听t-butyl cation is then quickly deprotonated to give 2-methylpropene (“isobutylene”) in an E1 reaction. To stop the isobutylene from Friedel-Crafting back to the听para– position, benzene (or toluene) is used as solvent (or co-solvent), which eventually results in formation of听t-butylbenzene.

This method听does听occasionally see use in synthesis. For example, in the synthesis of some derivatives, Hou et. al. were trying to dimerize a stilbene derivative. To cut down on the number of potential products, they found it useful to block two positions of a phenol with听t-butyl groups, which were later removed using AlCl₃, nitromethane, and toluene.

For more on the synthesis,听 check out (Nicolaou and Chen) Chapter 20. And while you’re there, don’t miss chapter 23!