Aromatic Synthesis (1) – “Order Of Operations”

by James

in Aromatic Reactions, Organic Chemistry 2, Synthesis

Up to now, we’ve covered electrophilic aromatic substitution [6 key reactions] [mechanism] [ortho-para-meta] and then the reactions of aromatic substituents [bromination & oxidation] [carbonyl reduction] [nitro reduction & Baeyer-Villiger].

So what?! All we’ve done is assemble a workshop full of gleaming new tools. We haven’t actually used them for anything yet!

So let’s start putting these reactions together in sequences with the goal of building specific molecules.

We’ll begin with a key principle for planning the synthesis of disubstituted aromatic molecules.

Why “Order Of Operations” Matters

The first lesson you learn in the synthesis of aromatic compounds is that “order of operations” matters.

Say you want to make this compound, m-bromonitrobenzene, from benzene:

When faced with a synthesis question that has a defined starting point like this,  my first question is always:

“What’s different? What bonds need to form and break going from the starting material to the product?” 

In this example, the bonds that form are C–NO2 and C–Br , and the bonds that break are C–H and C–H.

The second question I always ask is:

What reactions do I know that form and break these bonds?“.

In this case, the required reactions should be pretty straightforward : bromination (Br2, FeBr3) and nitration (HNO3, H2SO4)

So is that all there is to it? Almost.

This is where “order of operations” rears its potentially ugly head.

If we just barrel along, doing bromination first and nitration second, what happens?

Since the first reaction (bromination) installs an ortho-, para- director, the second reaction (nitration) will result in the undesired para- and ortho- products.

Since we want the meta product,  the first step should be installation of a meta– director (nitration) followed by bromination.

The bottom line is that after you have determined the bonds that need to form/break, and after you have a list of some of the reactions needed to form/break these bonds, you need to ask a third question when planning a synthesis:

“In what order do we run these reactions?”

(This doesn’t just apply to the synthesis of aromatic compounds – this is important for synthesis in general. )

Another example. Say we want to synthesize para-ethyl acetophenone (below):

The bonds that form here are two carbon-carbon bonds: C-CH2CH3 and C-C(O)CH, and the bonds that break are two C–H bonds.

Two reactions which could form and break these bonds are:

  • Friedel-Crafts acylation to make the C-C(O)CHbond (also with breakage of C–H)
  • Friedel-Crafts alkylation to make the C-CH2CH3 bond (with breakage of C–H)

As we said, however, this isn’t enough. We need to think about the order of operations.

The wrong way to do it is to do the Friedel-Crafts acylation first, which installs a meta director (the ketone), giving us the meta product upon Friedel-Crafts alkylation.

Noting the para– orientation of our desired product, the right way to plan the synthesis is to install the ortho-, para- director first (the ethyl group, via Friedel-Crafts alkylation) followed by Friedel-Crafts acylation:

In Summary

At the risk of restating what might be blindingly obvious by now, if you’re planning a synthesis of a molecule with an ortho-, para- director and a meta– director, you need to choose the order of operations wisely:

  • To obtain the para– (or ortho- ) product —-> install the ortho- , para- director first
  • To obtain the meta– product —-> install the meta- director first

In the next post, we’ll add another wrinkle to this “order of operations”; changing the nature of the directing groups.

Some Exercises

Here are three quiz examples. How would you synthesize each of these three molecules? Which operation comes first?

(The third example has three substituents – remember that when doing electrophilic aromatic substitution reactions on disubstituted benzenes, the most activating group “wins”. Post: Disubstituted Benzenes – The Strongest Donor “Wins”

Postscript: Further Thoughts On Order Of Operations

Are there cases where order of operations doesn’t really matter? Of course.

For our purposeswhen we are planning the synthesis of a disubstituted benzene with two ortho-, para- directors or two meta- directors, the order of operations doesn’t matter.

  • two halogen substituents (bromine and chlorine) para to each other? Take your pick of which reaction to do first.
  • nitro and sulfonyl oriented meta? For our purposes, either way is fine.

There is one complication, and since it isn’t addressed in many courses, I’m relegating it to this place at the bottom where relatively few people will read it.

The issue has to do with the Friedel Crafts alkylation and (to a slightly lesser extent) the Friedel-Crafts acylation reaction.

Friedel-Crafts Reactions Tend Not To Work On Aromatic Rings With meta– Directors

It turns out that Friedel-Crafts reactions don’t work particularly well when strong electron-withdrawing groups (i.e meta– directors, particularly NO2)  are present on the aromatic ring.

The issue isn’t so much that carbocations are poor electrophiles (alkyl carbocations are among the most powerful electrophiles known) – it’s that the reaction with electron-poor aromatic groups tends to be slower than side-reactions between the carbocations themselves.

Nitrobenzene doesn’t undergo Friedel-Crafts reactions at all.

So given the choice of putting NO2 on first or performing a Friedel-Crafts reaction, do the Friedel-Crafts first.






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