Generation Of Benzyne

Benzyne cannot be isolated, in fact, it has a lifetime of only 20 ns! This results from the high reactivity of the molecule, leading it to dimerise with itself if left longer than this [1].

As such, generation of benzyne in situ is of grave importance in its usefulness. Many different

techniques for benzyne generation exist, depending on the reaction conditions required:

De-Protonation[1]:

This is by far the simplest technique for benzyne generation, but is unfortunately amongst the least useful in modern synthetic strategies.

In this method, a mono-halogen substituted benzene is reacted with a strong base, often oxides, amine anions or carbon anions (eg. O2-, NH2- and CH3-)[1]. Under harsh conditions, the base deprotonates at the ortho position, leaving an anion species. This anion radical then 'falls' into

the ring and 'pushes' the halogen out.[2]

*Why does the base deprotonate at the ortho position? This position is most activated by the

electronegative halogen substituent, thus is most easily deprotonated.

*Why is this method not used? The harsh reaction conditions, in particular use of the strong base make it as such. Often, strong bases can act as strong nucleophiles. As such, this method often leads to unwanted final product generation upon reaction with the nucleophilic base,

rather than the desired ligand.[1]

Lanthanide Reduction[3]:

An alternative method to the de-protonation method is reaction with reducing lanthanide metals. Beginning with a di-halogenated benzene, lanthanide metal can be employed,

transferring a single electron to the most reactive halogen. This leads to loss of the halogen

anion and leaves a radical benzene species. A second electron transfer from lanthanide to benzene leads to a spin-paired lone pair, which collapses into the ring and leads to expulsion of the second halogen; thus forming benzyne. Driven by the oxidative potentials of the lanthanide metals, this reaction is very mild, but remains relatively novel.

Zwitterion Intermediate[4]:

One of the most common techniques applied in modern uses of o-benzyne is the zwitterion

approach.

This reaction is most commonly used with an anthranilic acid precursor. Reaction with NaNO2 and a strong acid, such as HCl yields the diazonium salt. Subsequent addition of base, eg. NaOH, deprotonates the carboxyllic acid, which, upon heat, is lost - as is N2 - yielding benzyne.

Due to the mild nature of this reaction, as well as the uncreative byproducts, this method of

benzyne generation allows for high yields of final product.

Kobayashi Protocol [5]:

Another widely used method for the generation of benzyne is the Kobayashi Protocol, in which the incredible strength of the Si-F bond is utilised.

Fluoride-induced 1,2-elimination of o-TMS aryl triflates under mild conditions has been found to lead to production of benzyne, driven by the Si-F bond strength (c. 220 KJ/mol increase over Si-C), as well as the release of (Me)3SiF(g). This reaction may be possible using Cl- anions (c. 60 KJ/mol increase over Si-C), but requires extreme conditions.

Grignard Reagents[6]:

Under relatively mild conditions benzyne can be generated using a Grignard intermediate. Addition of Mg metal to a dihalogen substituted benzene converts the most reactive halogen to a Grignard intermediate, followed by expulsion of the second via E2 elimination. This reaction is driven by production of X'MgX salts, where X'=halogen (X is typically Br).

In using this mechanism, other halogens within the reacting compounds must be considered so as to ensure correct Grignard formation.

This technique is vital to synthesis of arynes in the presence of reactive species, such as cyclopentadienyl anions.

References:

[1] Clayden, J. et al. (2001) Organic Chemistry, 1st ed. Oxford University Press, New York, USA.

[2] Tadross, P. (2006) Benzyne: The Adventures of a Reactive Intermediate. Stoltz Group Literature Presentation.

[3] Nishiyama, Y., Kawabata, H., Nishino, T, Hashimoto, K and Sonoda, N (2003) Dehalogenation of o-dihalogen substituted arenes and a,a'-dihalogen substituted o-xylenes with lanthanum metal, Tetrahedron, Vol 59. pp 6609-6614

[4] Carey, F. and Sundberg, R. (2000) Advanced Organic Chemistry: Reactions and Synthesis, 4th ed. Plenum Publishers, New York, USA. Pg 726

[5] Hayes, M., Shinokubo, H. and Danheiser, R. (2010) Intramolecular [4+2] Cycloadditions of Benzynes with Conjugated Enynes, Arenynes and Dienes, Organic Letters, Vol 7, pp 3917-3920.

[6]Ford,W (1971), Cycloaddition of Benzyne to Substituted Cyclopentadienes and Cyclopentadienyl Grignard Reagents.

Journal of Organic Chemistry,Vol 36, pp 3979‐3986.