Reactions and Uses of Benzyne

Alder-Ene Reaction: [1]

The alder ene reaction occurs between an enophile and an alkene, given that an alpha

hydrogen is available on the alkene.

In an alkene, the σ-bond of H-C can interact with the π bond in one of two ways: σ+π or σ-π. In the latter case, the phases of the orbitals corresponds favourably to those of the enophile π*

orbital, allowing for sufficient overlap and thus allowing the reaction to occur.

[2]

The reaction breaks the H-C σ bond, establishing two new σ bonds, as well as a new π bond. Due to the initial need to break the strong C-H σ bond, however, high temperatures are required for this reaction to occur.

hile very similar to the Diels-Alder mechanism in many ways, the Alder-Ene reaction is important in linear addition to aromatic compounds, rather than formation of polycyclic

species via the Diels-Alder mechanism, discussed below. Alder-Ene reactions with benzyne find use in many areas of synthetic chemistry, including drug design, natural product synthesis and

materials chemistry.

Diels-Alder Reaction:[1,3]

Similar to the Alder-Ene reaction, Diels-Alder reactions occur between a diene and a dienophile. In the case of benzyne, the dienophile, reactions yield polycyclic species with an aromatic component;

it is mainly for this reason that the Diels-Alder reaction is of such great importance to benzyne

chemistry.

In the Diels-Alder reaction, the sp2 hybrid bond of benzyne orientates itself to interact favourable with the π orbital of the diene. The reaction then occurs via a concerted, cyclic mechanism,

breaking two π bonds and producing two σ bonds.

The orientation of attack of this reaction leads to a stereospecific reaction. This, coupled to the addition of an aromatic component, has made Diels-Alder reactions amongst the most important reactions for drug design and natural product synthesis. Below are a few reactions for production of important pharmaceuticals [3]

Some other drugs synthesised via the Diels-Alder mechanism include:

Nucleophilic Addition[3]:

Amongst the simplest reactions underwent by benzyne is a simple nucleophilic addition reaction. In these reactions, nucleophiles (or electrophiles) attach benzyne, joining at either end of the triple bond (directed by steric effects). Contrary to normal aromatic additions, the addition of this first substitutent does not play a role in directing the addition of the second

substitutent; two substituents will always be added ortho to each other on the ring.

This has substantial importance in areas such as

• synthesis of strained ring systems:

• insertion of new c-c bonds:

• Synthesis of Substituted Indoles:

• Drug synthesis: eg Dynemicin A.

Carbon Nanotubes:

Benzyne has also been found to play a substantial role in modern nanotube and grephene research.

Gilchrist, et al. (1969)[4] demonstrated the use of benzyne as a me

thod for the nucleation and growth of carbon nanotubes, making use mainly of Kobayashi prot

ocol for benzyne generation. Others, such as Hoke et al. (1992)[5] used benzyne as a method via which to attach substituent groups to fullerenes, as well as a method via which to polymerise fullerenes.

Currently, the most important function of benzyne in nanotube research is as a 'tooth', allowing a mechanism to polymerise nanotubes, creating vast networks. Such networks have been vital in modern advances in technology (such as microchip production), water filters (graphene oxide filters), as well as much more![6, 7]

[6]

References:

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

[2] Organic Chemistry Portal. Accessed 6 Feb. 2012, Available from: http://www.organic-chemistry.org/namedreactions/alder-ene-reaction.shtm

[3] Tadross, P. (2006) Benzyne, The Adventures of a Reactive Intermediate. Stoltz Group Literature Presentaiton

[4] Gilchrist, T. and Rees, C. (1969) Carbenes, Nitrenes and Arynes., Nelson. London.

[5] Hoke, S., Molstad, J. Dilettato, D., Jay, M., Carlson, D., Kahr, B and Cooks, R. (1992), Jornal of Organic Chemistry, Vol 57, pp 5096.

[6] Globus, A., Bauschlicher, C., Han, J., Jaffe, R., Levit, C and Srivastave, D. (1998) Machine Phase Fullerene Nanotechnology, Nanotechnology, Vol. 9, pp 192-199.

[7]Deng, W., Xu, X., Goddard, W (2004) A Two Stage Mechanism of Bimetallic Catalyzed Growth of Single Walled Carbon Nanotubes, Nano letters Vol 4, No. 12, 2331-2335

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.

BENZYNE

WHAT IS BENZYNE [1]:

o-Benzyne is a highly reactive aryne intermedia

te. While most triple bonds consist of two pi-pi interactions, this is not the case with benzyne. I

nstead, the benzyne triple bond consists of one pi-pi bond, and one bond composed of interaction between two sp2 hybridised carbons. The latter bond creates enormous strain on the bond, leading to a very unstable intermediate. As a result of this reactiity, benzyne cannot be isolated and has been found to have a life-time of only 20ns!

The HOMO-LUMO gap about this triple bond is very small, allowing benzyne to function as both an electrophile and a nucleophile.

HOW WAS BENZYNE DISCOVERED [2]:

In the mid 19th century, reactions involving aromatic substitutions were yielding unexpected results. It was soon discovered by Wittig et al. the following:

In such a reaction, only two products were possible. This lead to the assumption of a zwitterionic intermediate; which was close, but not quite right...

Roberts then performed the classic '14C Labelling experiment'. In this experiment, one carbon, attached to the halogen, was a 14-C isotope. Upon reaction with sodium amide in ammonia, it was seen that only two products were possible, with the 14-carbon either at the substituted position, or ortho to it. It was reasoned that, if the zwitterionic intermediate were true, these two products would be produced in different ratios. This was not the case, however:

This lead to the proposed structure for benzyne:

References:

[1] Kit, H. (2005). The Chemistry of Benzyne: New Benzyne Precursor - Benzotrisoxadisilole. Hong Kong Baptist University. Available from: http://libproject.hkbu.edu.hk/trsimage/hp/02010305.pdf

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