Nucleophilic Aromatic Substitution (NAS)

Nucleophilic Aromatic Substitution (NAS)

In many ways, nucleophilic aromatic substitution is the mirror opposite of electrophilic aromatic substitution.

• In Nucleophilic Aromatic Substitution, an electron-poor aromatic ring is attacked by a nucleophile, resulting in a substitution reaction
• The reaction proceeds through a negatively charged (carbanion) intermediate
• The reaction is accelerated by the presence of electron-withdrawing groups on the aromatic ring
• The placement of electron withdrawing groups ortho- or para- to the leaving group results in faster reactions than does the placement of electron withdrawing groups meta- to the leaving group
• Fluorine can act as a leaving group (!) in nucleophilic aromatic substitution reactions, since it is quite electron-withdrawing and C-F bond breakage is not the rate-limiting step.

Table of Contents

1. Probably Not The Aromatic Substitution Reaction You Were Expecting
2. Introducing….Nucleophilic Aromatic Substitution
3. The Effect Of Substituents On The Ring
4. The Effect Of The Leaving Group
5. The Effect Of Substitution Pattern
6. The “Meisenheimer” Intermediate Provides A Clue To The Mechanism of Nucleophilic Aromatic Substitution
7. The Mechanism of Nucleophilic Aromatic Substitution
8. Why Is The para- Isomer Faster Than The meta- Isomer ? It’s All About Stabilizing Negative Charge
9. The Reaction Energy Diagram Of SNAr
10. A Few Examples
11. Summary: Nucleophilic Aromatic Substitution
12. Notes
13. Quiz Yourself!
14. (Advanced) References and Further Reading

1. Probably Not The Aromatic Substitution Reaction You Were Expecting

Let’s review electrophilic aromatic substitution (EAS). What have we learned?

• The aromatic ring acts as a nucleophile, and attacks an added electrophile E
• An electron-deficient carbocation intermediate is formed (the rate-determining step) which is then deprotonated to restore aromaticity
• electron-donating groups on the aromatic ring (such as OH, OCH₃, and alkyl) make the reaction faster, since they help to stabilize the electron-poor carbocation intermediate
• Lewis acids can make electrophiles even more electron-poor (reactive), increasing the reaction rate. For example  FeBr₃ / Br₂ allows bromination to occur at a useful rate on benzene, whereas Br₂ by itself is slow).

Everything we’ve learned so far about substitution on aromatic rings would teach us that it proceeds much faster with methoxybenzene than with nitrobenzene, and much faster with an electrophile like Cl₂ than with, say, an electron-rich nucleophile like NaOCH₃.

Which brings us to the reaction below. The aromatic ring  is electron-poor and we’re adding an electron-rich nucleophile.

What could happen here? Nothing, right?

“Nothing” is a good guess! Certainly, thinking of this as an electrophilic aromatic substitution, you’d be right in thinking that the answer to “what happens here?” is “jack squat”.

2. Introducing….Nucleophilic Aromatic Substitution

In fact, a substitution reaction does occur! (But, as you may suspect, this isn’t an electrophilic aromatic substitution reaction.)

In this substitution reaction the C-Cl bond breaks, and a C-O bond forms on the same carbon.

So while it is a substitution reaction, it has a few important differences:

• The species that attacks the ring is a nucleophile, not an electrophile
• The aromatic ring is electron-poor (electrophilic), not electron rich (nucleophilic)
• The “leaving group” is chlorine, not H+
• The position where the nucleophile attacks is determined by where the leaving group is, not by electronic and steric factors (i.e. no mix of ortho– and para- products as with electrophilic aromatic substitution).

In short, the roles of the aromatic ring and attacking species are reversed!

The attacking species (CH₃O^–) is the nucleophile, and the ring is the electrophile.

Since the nucleophile is the attacking species, this type of reaction has come to be known as nucleophilic aromatic substitution. 

3. The Effect Of Substituents On The Ring 

In nucleophilic aromatic substitution (NAS), all the trends you learned in electrophilic aromatic substitution operate, but in reverse.

The first trend to understand is that electron withdrawing groups (EWG’s) dramatically increase the rate of reaction, not decrease it.

From this, it follows that the more EWG’s there are, the faster the reaction.

For example, the rate of NAS for 2,4-dinitrophenyl chloride is about 10⁵ times faster than for p-nitrophenyl chloride. [Note 1]

(I don’t have a rate constant for 2,4,6-trinitrophenyl chloride readily available, but it is orders of magnitude faster still).

4. The Effect Of The Leaving Group

One of the most eye-opening aspects of nucleophilic aromatic substitution is noting that fluorine is often used as a leaving group. This is seen in Sanger’s reagent for sequencing peptides, to take one example (more on that below).

After all, given the stern tones we instructors use in Org 1 on this subject, the words  “FLUORINE IS NEVER A LEAVING GROUP IN S_N2 AND S_N1 REACTIONS” may as well have been carved on one of the stone tablets handed down to Moses on Mt. Sinai.

Here’s a thought: if even a “bad” leaving group like fluorine works in nucleophilic aromatic substitution, then surely a “better” leaving group like bromine or iodine would work even better. Right?

This is a good hunch.  It is also wrong – which does not make it a dumb idea,  only that organic chemistry is deep.

For one reaction studied [Note 3], F as the leaving group  was observed to be 3300 times faster than iodine !

And between chlorine, bromine, and iodine, the difference was only by a factor of about 3.

So what could be different about nucleophilic aromatic substitution that makes the rate of reaction much less sensitive to the identity of the leaving group than the S_N1 and S_N2 reactions?

Well, for one thing, this would suggest that, unlike the S_N1 and S_N2 reactions, C-F bond cleavage does not occur in the rate-determining step. This information is helpful in coming up with a mechanism for the reaction.

5. The Effect Of Substitution Pattern

Unlike in electrophilic aromatic substitution, there are no “ortho-,para-” or “meta-” directors. The position of substitution is controlled by the placement of the leaving group.

However that isn’t to say that the rate of the reaction isn’t affected by the relative position of the leaving group and the electron-withdrawing group.

For example, nucleophilic aromatic substitution of p-nitrophenyl fluoride is orders of magnitude faster than m-nitrophenyl fluoride, even though the NO₂ is closer to the leaving group and should presumably exert more of an inductive effect.

The ortho isomer is also faster than the meta by a large margin.

What’s going on? 

6. The “Meisenheimer” Intermediate Provides A Clue To The Mechanism of Nucleophilic Aromatic Substitution

In the course of adding nucleophiles to various electron-poor aromatic molecules with a leaving group, intermediates have been isolated. One of the first was isolated in 1902 by Jacob Meisenheimer, and the general name “Meisenheimer complex” is given to these intermediates.

The intermediate is the (non-aromatic) addition product between the aromatic ring and the nucleophile. In the case below, the negative charge is delocalized to an oxygen on one of the nitro groups:

Meisenheimer intermediates can be isolated and characterized. However, if heated, the compound goes on to form the final nucleophilic aromatic substitution product.

This is very suggestive, to say the least.

7. The Mechanism of Nucleophilic Aromatic Substitution

Taking all of these observations into account we can now propose a mechanism for this reaction.

The first step is attack of the nucleophile on the electron-poor ring to generate a negatively charged intermediate (e.g. the “Meisenheimer” intermediate, above)

Since this disrupts the aromaticity of the ring, it’s also the rate-limiting step:

In electrophilic aromatic substitution (EAS) we saw that electron-rich substituents stabilized the electron-poor intermediate.

But in nucleophilic aromatic substitution (NAS) the tables are turned!  Instead, the intermediate is electron-rich, and is stabilized by electron-withdrawing substituents, such as NO₂.

The second step in nucleophilic aromatic substitution is expulsion of the leaving group:

8. Why Is The para- Isomer Faster Than The meta- Isomer ? It’s All About Stabilizing Negative Charge

This two-step mechanism where addition is the rate-determining step helps to explain our earlier puzzle of why the reaction with para-nitro is faster than the meta- isomer.

• Note how the anion in the para- intermediate can be delocalized to the oxygen on the nitro group, putting a negative charge on (more electronegative) oxygen.
• In the meta- intermediate, the negative charge cannot be delocalized to the nitro group, and is stuck on (less electronegative) carbon.

(This also explains why addition is fast for the ortho– isomer).

It also helps to explain why fluorine substituents increase the rate of nucleophilic aromatic substitution: the rate determining step is attack on the aromatic ring, not breaking the very strong C-F bond. The highly electronegative fluorine pulls electron density out of the ring, activating it towards attack.

So even though breaking a C-F bond is generally not energetically favorable, this is compensated by the fact that it restores aromaticity.

[UPDATE: In the comments,  Matt brings up a very interesting  recent study that suggests that some nucleophilic aromatic substitution reactions that don’t have F as a leaving group may proceed through a concerted mechanism.  I would agree in considering this more advanced material is unlikely to be covered in most introductory courses, (except maybe Eugene’s) but very worthy of interest.]

9. The Reaction Energy Diagram Of SNAr

Putting it all together, we can sketch out a reaction-energy diagram for this mechanism that would look something like this:

(remember: transitition states are “peaks”, and intermediates are “valleys”. Intermediates can (at least theoretically) be isolated; transition states have partial bonds, only last a femtosecond, and can’t be isolated).

The nucleophile adds to the aromatic ring through transition state A (the rate limiting step) to give the negatively charged intermediate B, with a further input of energy (Ea) ascends to transition state C (loss of the leaving group, the fast step) and from there, the final product.

10. A Few Examples

Here’s three representative examples:

• The first is a straightforward nucleophilic aromatic substitution using an amine as a nucleophile.
• The second uses a stronger base (NaOH) to make a weaker base (the conjugate base of phenol) which attacks the electron-poor ring. (A variation of this reaction was used in a synthesis of the antibiotic vancomycin)
• The third example shows the N-terminus of a peptide reacting with 2,4-dinitrophenyl fluoride in a nucleophilic aromatic substitution reaction. Fred Sanger used this reagent to label the terminal residues in insulin, which led (after a lot of detective work Note 2], to the first reported sequence of a protein (and a Nobel Prize in chemistry in 1958).

11. Summary: Nucleophilic Aromatic Substitution

Well, now you’ve seen something we once said was impossible: fluorine as a leaving group. While we’re here, what other commandments from Org 1 can we possibly break?

How about putting a triple bond on an aromatic ring?

That’s next!

In the next post, we’ll cover a reaction that also qualifies as “nucleophilic aromatic substitution” although it goes through a completely different mechanism, involving this “triple bond”, above.

Next Post: Nucleophilic Aromatic Substitution (2): Arynes

Notes

Note 1. This is for the reaction below:

Note 2. Sanger’s detective work is detailed here.

Note 3. Link to the study is here.

Quiz Yourself!

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(Advanced) References and Further Reading

This is on nucleophilic aromatic substitution, specifically the addition-elimination reaction.

1. Ueber Reactionen aromatischer Nitrokörper
   Jakob Meisenheimer
   Liebig. Ann. Chem. 1902, 323 (2), 205-246
   DOI: 10.1002/jlac.19023230205
   The addition intermediates from SNAr reactions can frequently be detected or isolated, and are called Meisenheimer complexes, after Jakob Meisenheimer, who first demonstrated their formation.
2. The S_N mechanism in aromatic compounds. Part VII
   Peter Briner, Joseph Miller, M. Liveris, and (Miss)P. G. Lutz
   J. Chem. Soc., 1954, 1265-1266
   DOI: 10.1039/JR9540001265
3. The “Element Effect” as a Criterion of Mechanism in Activated Aromatic Nucleophilic Substitution Reactions
   F. Bunnett, Edgar W. Garbisch Jr., and Kenneth M. Pruitt
   Journal of the American Chemical Society 1957, 79 (2), 385-391
   DOI: 10.1021/ja01559a040
4. Nucleophilic substitution. Linear free energy relations between reactivity and physical properties of leaving groups and substrates
   Giuseppe Bartoli and Paolo Edgardo Todesco
   Accounts of Chemical Research 1977, 10 (4), 125-132
   DOI: 10.1021/ar50112a004
   These are mechanistic studies on the reaction, demonstrating that the order of reactivity is F > Cl > Br > I. In nucleophilic aromatic substitution, the formation of the addition intermediate is usually the rate-determining step so the ease of C-X bond breaking does not affect the rate.
5. NUCLEOPHILIC AROMATIC SUBSTITUTION OF ARYL FLUORIDES BY SECONDARY NITRILES: PREPARATION OF 2-(2-METHOXYPHENYL)-2-METHYLPROPIONITRILE
   Stéphane Caron, Jill M. Wojcik, and Enrique Vazquez
   Org. Synth. 2002, 79, 209
   DOI: 10.15227/orgsyn.079.0209
   A procedure in Organic Syntheses for an S_NAr reaction, featuring nucleophilic displacement of an aryl fluoride.
6. The terminal peptides of insulin
   Frederick Sanger
   Biochemical Journal (1 January 1949) 45 (5): 563–574
   DOI: 10.1042/bj0450563
   One of this historically most significant examples of aromatic nucleophilic substitution is the reaction of amines with 2,4-dinitrofluorobenzene. This reaction was used by Frederick Sanger (who won 2 unshared Nobel Prizes in Chemistry) to develop a method for identification of the N-terminal amino acid in proteins.
7. Concerted nucleophilic aromatic substitutions
   Eugene E. Kwan, Yuwen Zeng, Harrison A. Besser & Eric N. Jacobsen
   Nature Chemistry volume 10, pages 917–923 (2018)
   DOI: 10.1038/s41557-018-0079-7
   This is at the cutting edge of chemistry – the authors use interesting NMR experiments to assert that S_NAr reactions proceed through concerted rather than stepwise mechanism.