Reactions of Aromatic Molecules
Synthesis of Benzene Derivatives (2) – Polarity Reversal
Last updated: October 14th, 2022 |
In this article we go into detail on how to do these “reversals of polarity”:
- Reduction of nitro groups (NO2) to amines converts a meta director to an ortho-, para– director
- Reduction of ketones (C=O) to alkanes converts a meta director to an ortho-, para– director
- The Baeyer-Villiger reaction converts a ketone (meta- director) to an ester (ortho-, para– director)
- Benzylic oxidation with KMnO4 converts an ortho-, para– director to a meta- director
Table of Contents
- Reminder: The “Order of Operations” Is Important
- What Do We Do When Directing Groups Don’t Direct The “Right Way” ?
- Ortho-, Para- Directors From Meta- Directors: 3 Examples
- Meta- Directors From Ortho-, Para- Directors
- Summary: Synthesis of Benzene Derivatives – Polarity Reversal
- Quiz Yourself!
Last time we talked about the importance of choosing the correct “order of operations” in the synthesis of aromatic compounds [See post: Aromatic Synthesis (1): Order of Operations].
- To obtain the para– (or ortho- ) product —-> install the ortho- , para- director first
- To obtain the meta– product —-> install the meta- director first
Alright. Now let’s throw a curveball.
No two-step sequence of electrophilic aromatic substitution reactions will give you this product!
So what do we do?
Not to worry. There’s a whole other bag of tricks we haven’t used yet – reactions that modify aromatic substituents – that will provide us with the solution to problems like this one.
- reduction of nitro groups (NO2) to amines (NH2) using Pd-C/H2 , Zn / HCl and other methods.[See post]
- reduction of ketones to alkyl groups using the Wolff-Kishner, Clemmensen, or other methods [See post]
- Baeyer-Villiger oxidation of ketones to esters using peroxyacids (e.g. m-CPBA).[See post]
Having these reactions available to us greatly expands the number of products we can build from benzene.
Let’s think backwards. Having access to these reactions means that if there is an amine in a product we wish to make, it can be obtained from reduction of a nitro group.
(The specific reactions to use in the forward direction are essentially equivalent, for our purposes). We can use a reducing metal like Zn, Fe, or Sn with acid, or catalytic hydrogenation over palladium or platinum.
The nitro group, in turn, can be installed through electrophilic aromatic substitution (HNO3 + H2SO4).
We can apply the same backwards-looking process toward alkyl groups. While alkyl groups can be installed directly using Friedel-Crafts alkylation, remember that carbocation rearrangements can occur with longer-chain primary alkyl halides. Previously, we saw that long alkyl chains can be installed by performing a Friedel-Crafts acylation first, followed by reduction of the ketone (a.k.a. “The Great Friedel-Crafts Workaround”). [See post: The Friedel-Crafts Reactions]
So any time you see an alkyl group in a target molecule, by all means consider the (straightforward) Friedel-Crafts alkylation, but also take a moment to think about how it could be installed through working backwards to a ketone.
Now, back to our regularly scheduled problem.
Clearly we can’t build this molecule directly through two consecutive electrophilic aromatic substitution reactions.
For more practice, try working on these examples which require similar reasoning:
[more discussion of these problems in Note 2]
Let’s look at a different type of problem. Below, we have a carboxylic acid (meta- director) para to a nitro group (another meta director). So how can we design a synthesis that gets these two meta- directors para– to each other?
- oxidation of alkyl groups with KMnO4 to give carboxylic acids. [see post: Reactions on the “Benzylic” Carbon]
[Note: although this doesn’t strictly convert an ortho-, para- director to a meta- director, it’s also worth looking at benzylic bromination as another route to meta- directors, since alkyl halides are so versatile. We’ll cover this in Note 1 ]
Going back to our example, we see that working backwards from the carboxylic acid gives us an alkyl group (so long as it’s not t-butyl, the exact identity isn’t important, since KMnO4 chews up all alkyl groups with at least one benzylic C-H bond to give carboxylic acids).
Synthesis of this para-disubstituted molecule requires that we start with the Friedel-Crafts alkylation, followed by nitration.
(This is by no means the only way to do it! One of the fun parts about synthesis is that there are multiple ways to approach the same problem!) (Note 3)
Planning the right “order of operations” with reactions that “reverse the polarity” of aromatic side chains will allow you to synthesize most of the molecules you will encounter in synthesis problems.
We didn’t go into the synthesis of trisubstituted molecules, but the same strategies also apply, along with the key principle “the strongest donor wins”
(Additionally, we haven’t really considered nucleophilic substitution reactions here, but they could concievably be worked in too. In synthesis everything is fair game unless you’re told otherwise).
Before we do a few practice problems, there’s one last trick to cover.
In the next post, we’ll show a strategy for doing this, using “blocking groups”.
Benzylic bromination can be a useful precursor to meta- directors, although somewhat longer sequences of reactions are usually required to get to the desired product.
However, we have learned how to convert “benzylic” alkyl groups into alkyl halides. And if there’s one thing you learn in Org 1, it’s that alkyl halides can undergo a ton of different reactions. [this post has a “reaction map” for alkyl halides]
- One way to get to the ketone from the alkyl bromide would be to perform an SN2 of the benzyl bromide with hydroxide (in a polar aprotic solvent) to give an alcohol, which could be oxidized to a ketone.
- Another way would be to eliminate the halide (E2) with strong base to give an alkene, followed by hydration (oxymercuration or H3O+) to give an alcohol, which could be oxidized similarly.
The ketone is just one of other possible examples. As the pathways below try to show, alkyl halides are a gateway not only to the many compounds possible from nucleophilic substitution reactions, but also to those arising from reactions of alkenes and alcohols.
Worked example #1 .
Worked example #2
Note 3 – For instance another way to do it (that doesn’t involve EAS) would be to make the carboxylic acid through reaction of a Grignard with CO2. The Grignard would come from Br or Cl, which are ortho-, para- directors. So: bromination, nitration, Grignard formation, then add CO2.