summary of nucleophilic aromatic substitution reactions

• 3. Substituents: Electron-withdrawing groups are critical to polarize the ring and stabilize the negative charge in the Meisenheimer complex.
• 4. & 5. Alternative mechanisms: Rarely, the elimination occurs before addition. Strong bases can promote elimination-addition mechanisms (via benzynes) while diazonium compounds can undergo S_N1-like substitutions (via carbocations).

1. The S_NAr Substitution Mechanism

The nucleophilic aromatic substitution is a variation of a reaction we know well: the electrophilic aromatic substitution.

They achieve similar goals but using the opposite reactivity!

What’s the goal? Replacement or substitution of an existing group with a new one. In electrophilic substitutions, we are replacing C-H bonds (H departing as a proton or H⁺) with a new C-E bond by adding a reactive electrophile.
In nucleophilic substitutions, we cannot do this as this would require H^– to act as a leaving group. Instead, we are replacing C-LG bonds – where LG is typically a electronegative group like a halogen – with C-Nuc bonds by adding a nucleophile.

Why opposite reactivity? Nucleophilic aromatic substitution uses nucleophiles to attack electron-deficient, electrophilic aromatic rings. Simply put, the nucleophile is “the minus” and the ring is “the plus”.
For electrophilic aromatic substitution, it’s the opposite: we use electron-rich aromatic rings (minus) that react with electrophiles (plus).

Nucleophilic aromatic substitutions are never S_N2 (‘backside attack’) and usually start with addition of the nucleophile. Rarely, the LG departs first (see below).

We can construct an illustrative energy diagram based on the mechanism above. Similar to the electrophilic case, the first addition is the rate-determining step with the highest activation energy. This makes a lot of sense because the ring loses its aromaticity, so there is a considerable energy barrier.

The ease of this addition (i.e., the energy of TS1) and the stability of the carbanion intermediate / Meisenheimer complex depends on the leaving group and ring substituents. Let’s review this in some additional detail.

2. The Leaving Group in Nucleophilic aromatic substitution

Nucleophilic aromatic substitutions can work with a broad set of leaving groups, but most common are halides like chloride of fluoride. Leaving groups have two roles:
1. Obvious: They need to be able to depart after the initial addition because otherwise, it would not be a C-Nuc substitution of C-LG
2. Less obvious: Similar to activating substituents, they accelerate the initial addition by increasing the electrophilicity of the carbon they are bound to.

C-F bonds are very strong and difficult to break – thus, fluoride F^– is not a good LG. However, its inductive effect (σ acceptor due to high electronegativity) increases the positive polarization of carbon and its reactivity with nucleophiles.

There are many cases in organic chemistry where two or more factors are at play. Fluoride is a rubbish leaving group in the second step but the best activator for the first step. Because the first step is the critical one (highest energy/ rate-determining), the pro outweighs the con.

Unsurprisingly, on the other end of the spectrum, iodide is a bad activator because the C-I bond is much less polarizes than the C-F bond. This explains why aryl iodides are much, much less reactive.

Halides are special snowflakes. You will benefit greatly from understanding their EN, acidity (and leaving group quality) and bond strengths. Also, remember their role in S_EAr reactions: they direct ortho and para but are deactivating overall.

3. Substituent Effects in Nucleophilic aromatic substitutions

For nucleophilic aromatic substitutions, any existing groups at the ring are even more important than in in electrophilic aromatic substitutions.

Electron-rich rings are great for electrophilic reactions (these are more nucleophilic and can stabilize the intermediary cation) do not participate in nucleophilic aromatic substitutions. If the ring is ‘already negative’, why would it want another negative charge to come close to it?

Anion-stabilizing / electron-withdrawing groups (π acceptors) ortho or para to a potential LG activate the system towards nucleophilic aromatic substitution.

Conversely, electron-poor rings do not participate in electrophilic reactions but are great for nucleophilic substitutions (these rings are electrophilic and can stabilize the intermediary anion).

The most potent activating groups are nitro, sulfone, nitriles and carbonyl groups. If they are ortho or para, we can draw stabilized resonance structures where the negative charge benefits from delocalization into the substituents’ π system.

Usually, we want at least one electron-withdrawing (activating) group on the ring. Rarely, ‘brute force’ reactions also happen in unactivated systems. One example is the old-school synthesis of phenol using the Dow process. The more activating groups, the easier and better the reaction.

Wrapping up on S_NAr (addition-elimination), remember the nitro group for its unique ability to bridge electrophilic and nucleophilic aromatic substitutions. Once introduced through electrophilic substitution, it acts deactivating for subsequent electrophilic reactions but acts activating for other, nucleophilic substitutions (if the starting material allows it by having a leaving group). Here’s an example. Nitro groups can convert to other functional groups (here: reduction to anilines) so they can be very handy.

4. Elimination-Addition Mechanism (Benzyne)

Speaking of unactivated systems, there is a different way that these undergo substitutions. Using strongly basic nucleophiles can invert the sequence of steps: instead of addition-elimination, we see elimination-addition.

This process is rather strange and unintuitive. In absence of any other acidic protons, the base deprotonates a proton ortho to the leaving group. The base needs to be strong because the resulting carbanion is not stable at all. It’s not too happy and continues to react further by kicking out the leaving group. In these reactions aryl fluorides perform way worse than bromides or chlorides because of the weak leaving group quality of fluoride.

This forms our second intermediate, a so-called benzyne – a benzene ring with a triple bond. Alkynes usually strive to be fully linear but embedding it in a ring makes this impossible. Accordingly, benzyne is rather strained but it can exist as a fleeting intermediate.

Now that we covered the elimination of the C-LG group, let’s get to the addition. These reactions use an excess of base / nucleophile, so even after deprotonation, we have a lot of reactant available. Nucleophilic attack to the weak triple bond creates the C-Nuc bond, giving a final intermediate that looks similar to the anion formed in the first deprotonation.

Elimination-addition reactions can lose their regiospecificity. The nucleophile can be introduced at a different carbon than the original one bearing the LG.

Reactions of substituted aryl halides can lead to mixtures of regioisomers. This is a major difference to the S_NAr mechanism, where one starting material can only give one product (Nuc ends up on the same carbon as the LG was attached to).
These details deserve a separate discussion. Electronic and steric factors can introduce regioselectivity of the addition. If the substituent is a simple alkyl group like shown here, the addition is not really regioselective (1:1 mixture of isomers).

5. S_N1 mechanism for nucleophilic aromatic substitution

A final exceptional mechanism is observed for diazonium compounds. Similar to the elimination-addition, this step does not require the activating substituents that we’ve discussed for the normal S_NAr (addition-elimination) mechanism.

It’s totally different from the other two mechanisms which had anionic intermediates (Meisenheimer complex and benzene anions, respectively) – it features a cationic intermediate!

Why does this work? When warmed, diazonium salts release nitrogen gas, the best of all leaving groups. With this energy gain, the aromatic ring gladly temporarily turns into an aryl cation. This should remind you of the unimolecular substitution mechanism where the LG departs first, followed by addition of the nucleophile.

The Balz–Schiemann reaction is a name reaction using this S_N1-like pathway to create aryl fluorides. This means we can use nucleophilic aromatic substitution to make … starting materials for more nucleophilic aromatic substitution!
Today I learned: Both German chemists Balz and Schiemann had the first name Günther (now this is what I call valuable information).

Beware, not all aryl diazonium derivatizations go through cationic intermediates. Instead of being polar, the well-known Sandmeyer reaction is a radical process.

I might explain both of these in future – in the mean time, just search them on Google to make the connection.

nucleophilic aromatic substitution Examples

Here are some additional examples of aromatic substitutions. Two reactions differ from the rest from a mechanistic perspective. Which?

To minimize the spoilers and add some more space between the questions and the solutions – thanks for reading this article!
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