Nucleophilic Aromatic Substitution (2) – The Benzyne Mechanism

In this post we’ll discuss nucleophilic aromatic substitution, but with a new twist; a nucleophilic aromatic substitution that passes through a strange-looking intermediate called an aryne (a generic term for a family of molecules that includes benzyne).

Table of Contents

1. Nucleophilic Aromatic Substitution – A Quick Recap
2. A “Nucleophilic Aromatic Substitution” In Name, But By A Different Mechanism
3. The “Benzyne” Intermediate
4. Reaction of Substituted Benzyne – “Arynes”
5. Benzyne Undergoes Diels-Alder Reactions
6. The Structure of Benzyne
7. Summary: Nucleophilic Aromatic Substitution via Benzyne
8. Notes
9. Quiz Yourself!
10. (Advanced) References and Further Reading

1. Quick Recap: Nucleophilic Aromatic Substitution

Previously [see: Nucleophilic Aromatic Substitution] we saw that electron-poor aromatic rings containing a leaving group can undergo substitution with electron-rich nucleophiles.  We saw that the mechanism proceeds through addition of a nucleophile to the aromatic ring (via an electron-rich intermediate) followed by loss of a leaving group, in a process sometimes called, “addition-elimination”.

Importantly, the only substitution product is the one where the nucleophile ends up attached to the same carbon as that bearing the leaving group.  (This differentiates it from electrophilic aromatic substitution, where a mixture of ortho-, para–  and meta- products can be obtained.)

2. A “Nucleophilic Aromatic Substitution” In Name, But By A Different Mechanism

Although the “addition-elimination” mechanism for nucleophilic aromatic substitution has been known since at least 1902 , it became increasingly clear in the first half of the twentieth century that certain reactions classified as “nucleophilic aromatic substitution” appeared to proceed through a different mechanism altogether.

For example, it was found that treating chlorobenzene with sodium amide (NaNH₂) in liquid ammonia (boiling point = –33°C) resulted in the rapid formation of aminobenzene (“aniline”):

An addition-elimination mechanism here doesn’t seem right, considering that nucleophilic aromatic substitution reactions with far stronger electron withdrawing groups (e.g. NO₂, rather than Cl) require higher temperatures and longer reaction times.

Another observation was that no reaction occurred under these conditions when the ortho- positions were attached to alkyl groups. A hydrogen is necessary at one of these positions for the reaction to proceed.

(note – NaNH₂ and KNH₂ can be considered to be essentially the same for our purposes)

A second observation was that in the case below only the ortho- and meta- products formed, and never the para– .

3. The Benzyne Intermediate

Various intermediates were proposed to explain these results, but then in 1953 John D. Roberts (then at MIT) nailed it by  publishing one of the most elegant chemical experiments of all time.

He and his team synthesized chlorobenzene but with a special difference: the carbon attached to the chlorine was a radioactive isotope of carbon (¹⁴C), not carbon (¹²C).

This radioactive carbon atom served as an atomic “label”, which allowed them to conclusively determine if substitution happened exclusively at the carbon bearing the leaving group.   (how? [Note 4]) 

Roberts’ group carried out the reaction under conditions reported previously, and found that about 50% of the product ended up with the NH₂ attached to the labelled carbon, and the other 50% had the NH₂ on the carbon adjacent to the label.

This is not consistent with an addition-elimination mechanism!

In fact, the roughly 50:50 ratio of products implies the involvement of a symmetrical intermediate which is attacked equally on either side.

Roberts’ proposal – which has stood the test of time – was the involvement of a short-lived intermediate bearing a carbon-carbon triple bond:  “Benzyne” ! 

At first glance, this seems crazy. A triple bond in an aromatic ring?

Well, it’s not quite a true triple bond in the way that we’re familiar with (i.e. with alkynes). Instead of an overlap between two 2p orbitals (as in an alkyne) the “triple bond” is formed through overlap of two adjacent sp² orbitals in the plane of the ring (i.e. at right angles to, and completely independently of, the aromatic pi system).

Since these orbitals actually point away from each other, the overlap between them is poor, resulting in a “triple bond” that is actually very weak.

The strain energy of benzyne has been estimated to be about 50 kcal/mol – more strained than cyclopropane (28 kcal/mol), and only slightly less strained than cyclopropene (54 kcal/mol).

An intuitive way to think about it is to imagine the involvement of two resonance structures (far left and far right, below) that make strong (and equal) contributions to the overall resonance hybrid, such that both carbons can be considered “electrophilic”.

[A more rigorous way to treat it is from a molecular orbital perspective – a weak bond results in a low-energy LUMO, and therefore a lower energetic barrier to attack by nucleophiles]. 

However strange it might look, the benzyne intermediate explains all of these important observations, and more.

• In the first step (elimination) a strong base removes a hydrogen from the carbon adjacent to that bearing the leaving group, resulting in an elimination reaction that forms the triple bond. This explains why no reaction occurs when both positions adjacent to the leaving group lack hydrogen!

• In the second step (addition), attack of the can come at either side of the triple bond, resulting in about a 1:1 mixture of the product with NH₂ attached to the labelled carbon (A) and NH₂ adjacent to the labelled carbon (B).

Although it’s tempting to use ^–NH₂  as nucleophile, the more likely nucleophile here is the solvent, NH₃, which readily reacts with the extremely reactive benzyne intermediate. After attack of NH₃, proton transfer occurs to result in the neutral product. [note that although intramolecular proton transfer is shown below, it’s also possible to show it occurring through an intermolecular mechanism]

4. Reactions Of Substituted Benzyne (“Arynes”)

What happens when a substituent is present on benzyne? [Note: Just like substituted compounds of benzene are called “arenes”, substituted benzynes are called “arynes”. ]

When a substituent is present, an unsymmetrical aryne will result, and at least two products (and sometimes three) can potentially form. In the example below, attack of NH₃ at carbon A results in the ortho product, and attack of NH₃ at carbon B results in the meta product.

So how do substituents on the ring affect addition to the triple bond?

Since the aromatic pi-system is at right angles to the triple bond, what’s NOT relevant is the ability to donate a lone pair to the ring (like OCH₃) , or accept a lone pair from it (like NO₂).

However, inductive effects are still relevant (i.e. electron-withdrawing effects that occur through single bonds).

Why?  Addition to the triple bond creates a negative charge on carbon, and electron-withdrawing groups stabilize negative charge: the closer, the better.

So a key principle in the addition of nucleophiles to arynes is that  addition tends to happen so as to place the negative charge closer to an electron-withdrawing substituent. 

Two key examples.

• When the triple bond is between the meta and para carbons, attack will favor the para product, since the negative charge ends up on the meta carbon (closer than para).
• When the triple bond is between the ortho and meta carbons, attack will favor the meta product, since the negative charge ends up on the ortho carbon (closer than meta)

Note that this only applies for electron-withdrawing groups like CF₃, not electron-donating groups like CH₃ or alkyl. What’s interesting is that OCH₃ behaves like an electron-withdrawing group in these examples, since the oxygen lone pairs can’t interact with the triple bond.

See the [Note 1] for some more examples.

5. Benzyne Undergoes Diels Alder Reactions

Benzyne can also react with dienes in Diels-Alder reactions.  The triple bond of benzyne acts as a dienophile:

6. The Structure Of Benzyne

For many years benzyne defied attempts at isolation and characterization, its existence inferred through trapping experiments with nucleophiles or dienes. It lives fast and dies young.

Eventually, benzyne was trapped at 6K (i.e. six degrees above absolute zero) in frozen argon and studied through various spectroscopic methods.  The triple bond is about 1.26 Å, longer (and weaker)  than that in ethyne (1.20 Å) and the adjacent C-C bond is about 1.38 Å , slightly shorter than that in benzene.

(See reference). All the other C-C bonds are within 0.01 Å of the bond lengths in benzene.

7. Summary: Nucleophilic Substitution Reactions Via Benzyne

There is one final type of aromatic substitution reaction for us to consider – a family of reactions called the Sandmeyer reaction that uses nitrogen gas (N₂) as the leaving group. More on that next time.

Next Post: Reactions of Diazonium Salts and The Sandmeyer Reaction

Notes

• Some other examples of substitution
• Methods for generating benzyne
• Roberts’ degradation study

Some other examples of substituted benzynes

When an aryne is made from p-chlorotoluene, a mixture of para and meta products is obtained.

When an electron-withdrawing substituent like CF₃ is used instead of CH₃, more of the para is formed – about 60:40, favoring the para. (Statistics would favor the meta by 2:1).

This is because attack at the para position places the negative charge closer to the electron withdrawing group.

Interestingly,  OCH₃ gives about the same ratio as CF₃ (60:40). This means that oxygen is acting purely as an electron-withdrawing group, not a pi-donor. (Further proof that the oxygen lone pair can’t interact with the triple bond. )

With the ortho-series, the results are even more dramatic. With CH₃, about an equal mixture of ortho and meta products is obtained. With CF₃ and OCH₃, only the meta is observed.

Some ways of generating benzyne

Benzyne can be generated in several other ways besides deprotonation with a strong base like NaNH₂ or KNH₂.

Grignard reagents behave much like carbanions. So a different path to benzyne formation is to start with a dihalobenzene like o-bromofluorobenzene and treat it with magnesium metal. The Grignard forms, and then this “anion” can displace even a good leaving group like fluorine to give the triple bond:

Another path is to generate a leaving group that can leave irreversibly as a gas, like CO₂ or N₂.

In the first reaction below, UV light breaks the weak O-O bond, and then homolytic dissociation results in loss of two CO₂ molecules to give benzyne.

In the second example, commercially available (and cheap) anthranilic acid is converted into a diazonium ion with HNO₂ and HCl. Heat results in loss of CO₂ and N₂:

This is just the tip of the iceberg. For more reading, this presentation on arynes by Eric Welin of the Macmilllan group at Princeton is an excellent introduction.

Degradation study.

Today, the results of Roberts’ labelling experiment could be determined in about 5 minutes through a technique called Nuclear Magnetic Resonance, or NMR.

But in 1954, this technique didn’t exist. So it was necessary to determine the ratio by breaking the products down into simpler components via well-understood chemical reactions, a technique known as “degradation”.

Aniline was converted into phenol through diazonium salt formation and substitution with water. Hydrogenation with Raney nickel under high pressure gave cyclohexanol, which was then oxidized to cyclohexanone with chromic acid. A Schmidt reaction converted cyclohexanone into a lactam, which was hydrolyzed to the free acid. A second Schmidt reaction then liberated CO₂, which was trapped with barium hydroxide. The radioactivity of the CO₂ and the diamine products were found to be roughly equal  (and each about half of the total reactivity of the acid precursor), thus confirming that attack of the nitrogen occurred at two different carbons.

Our chemical ancestors had to perform the labor of Job just to get a structure.

The person who did more than anyone else to develop and popularize the use of NMR as a technique for structure determination of organic compounds, and thereby free us from this misery?

John Roberts, who began working on it shortly after this benzyne study was published.

Quiz Yourself!

Click to Flip

Click to Flip

(Advanced) References And Further Reading

In these first two papers, Nobel Laureate Georg Wittig describes reactions of o-fluorophenyllithium and proposes they go through a zwitterionic intermediate (although in paper 2 he does also use a triply bonded structure for o-benzyne).

1. Über die Bildung von Diphenyl aus Fluorbenzol und Phenyl‐lithium (IV. Mitteil. über Austauschreaktionen mit Phenyl‐lithium)
   Georg Wittig, Gustav Pieper, Gerhard Fuhrmann
   Ber. 1940, 73 (11), 1193-1197
   DOI: 10.1002/cber.19400731113
2. Phenyl-lithium, der Schlüssel zu einer neuen Chemie metallorganischer Verbindungen
   Georg Wittig
   Naturwissenschaften November 1942, Volume 30, Issue 46–47, pp 696–703
   DOI: 1007/BF01489519These papers are classics by Prof. J. D. Roberts in which he used ¹⁴C-labeled chlorobenzene and KNH₂ to prove the intermediacy of benzyne due to scrambling of the ¹⁴C label after the reaction.
3. REARRANGEMENT IN THE REACTION OF CHLOROBENZENE-1-C14 WITH POTASSIUM AMIDE
   John D. Roberts, Howard E. Simmons Jr., L. A. Carlsmith, and C. Wheaton Vaughan
   Journal of the American Chemical Society 1953 75 (13), 3290-3291
   DOI: 1021/ja01109a523
4. The Mechanism of Aminations of Halobenzenes
   John D. Roberts, Dorothy A. Semenow, Howard E. Simmons Jr., and L. A. Carlsmith
   Journal of the American Chemical Society 1956 78 (3), 601-611
   DOI: 1021/ja01584a024
5. TRIPTYCENE
   Georg Wittig
   Org. Syn. 1959, 39, 75
   DOI: 10.15227/orgsyn.039.0075
   This procedure in Organic Syntheses, a source of reliable and independently tested experimental synthetic organic chemistry procedures, is also from Georg Wittig and is a classical method for preparing benzyne.
6. FLUORIDE-INDUCED 1,2-ELIMINATION OF O-TRIMETHYLSILYLPHENYL TRIFLATE TO BENZYNE UNDER MILD CONDITIONS
   Yoshio Himeshima, Takaaki Sonoda, Hiroshi Kobayashi
   Lett. 1983, 1211-1214
   DOI: 10.1246/cl.1983.1211
   This is an extremely influential paper in organic chemistry, since this chemistry enables the generation of benzyne under extremely mild conditions (room temperature or below).
7. THE DIRECT ACYL-ALKYLATION OF ARYNES [PREPARATION OF METHYL 2-(2-ACETYLPHENYL)ACETATE]
   David C. Ebner, Uttam K. Tambar, and Brian M. Stoltz
   Org. Syn. 2009, 86, 161
   DOI: 10.15227/orgsyn.086.0161
   An example of a modern synthetic procedure involving benzyne, using the chemistry developed by Kobayashi (ref. 6). Prof. Brian Stoltz (Caltech) has developed (and continues to develop) many interesting synthetic methodologies using benzyne.
8. Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions
   G-Yoon J. Im, Sarah M. Bronner, Adam E. Goetz, Robert S. Paton, Paul H.-Y. Cheong, K. N. Houk, and Neil K. Garg
   Journal of the American Chemical Society 2010 132 (50), 17933-17944
   DOI: 10.1021/ja1086485
   Prof. Neil Garg (UCLA) did his PhD with Prof. Stoltz and has extended the benzyne concept to other heterocycles, such as indole, notably developing chemistry based on ‘indolyne’.
9. One Century of Aryne Chemistry
   Hans Henning Wenk Dr., Michael Winkler Dipl.‐Chem., Wolfram Sander Prof. Dr.
   Chem. Int. Ed. 2003, 42 (5), 502-528
   DOI: 10.1002/anie.200390151
   Nice review on aryne chemistry.