{"id":11863,"date":"2018-09-17T06:00:19","date_gmt":"2018-09-17T10:00:19","guid":{"rendered":"https:\/\/www.masterorganicchemistry.com\/?p=11863"},"modified":"2026-04-18T06:42:08","modified_gmt":"2026-04-18T11:42:08","slug":"nucleophilic-aromatic-substitution-2-benzyne","status":"publish","type":"post","link":"https:\/\/www.masterorganicchemistry.com\/2018\/09\/17\/nucleophilic-aromatic-substitution-2-benzyne\/","title":{"rendered":"Nucleophilic Aromatic Substitution (2) – The Benzyne Mechanism"},"content":{"rendered":"

In this article 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\u00a0<\/strong>(a generic term for a family of molecules that includes\u00a0benzyne<\/strong>).<\/p>\n

\"summary-formation<\/a><\/p>\n

Table of Contents<\/strong><\/p>\n

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

    <\/a>1. Quick Recap: Nucleophilic Aromatic Substitution<\/h2>\n

    Previously [see: Nucleophilic Aromatic Substitution<\/a>]<\/em> we saw that electron-poor aromatic rings containing a leaving group can undergo substitution with electron-rich nucleophiles<\/strong>.\u00a0 We saw that the mechanism proceeds through addition of a nucleophile to the aromatic ring (via<\/em> an electron-rich intermediate) followed by loss of a leaving group, in a process sometimes called, “addition-elimination”.<\/p>\n

    \"nucleophilic<\/p>\n

    Importantly, the only substitution product is the one where the nucleophile ends up attached to the same carbon as that bearing the leaving group<\/strong>.\u00a0 (This differentiates it from electrophilic aromatic substitution, where a mixture of\u00a0ortho<\/em>-,\u00a0para<\/em>–\u00a0 and\u00a0meta-\u00a0<\/em>products can be obtained.)<\/p>\n

    <\/a>2. A “Nucleophilic Aromatic Substitution” In Name, But By A Different Mechanism<\/strong><\/h2>\n

    Although the “addition-elimination” mechanism for nucleophilic aromatic substitution has been known since at least 1902\u00a0, 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.<\/p>\n

    For example, it was found that treating chlorobenzene with sodium amide (NaNH2<\/sub>) in liquid ammonia (boiling point = \u201333\u00b0C) resulted in the rapid formation of aminobenzene (“aniline”):<\/p>\n

    \"nucleophilic<\/p>\n

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

    Another observation was that no reaction occurred under these conditions when the ortho-\u00a0<\/em>positions\u00a0were attached to alkyl groups. A hydrogen is necessary at one of these positions for the reaction to proceed.<\/p>\n

    \"no<\/p>\n

    (note – NaNH2<\/sub> and KNH2<\/sub> can be considered to be essentially the same for our purposes)<\/em><\/span><\/p>\n

    A second observation was that in the case below only the\u00a0ortho-\u00a0<\/em>and\u00a0meta-\u00a0<\/em>products formed, and never<\/strong> the\u00a0para<\/em>– .<\/p>\n

    \"in<\/p>\n

    <\/a>3. The Benzyne Intermediate<\/h2>\n

    Various intermediates were proposed to explain these results, but then in 1953 John D. Roberts<\/strong> (then at MIT) nailed it by\u00a0 publishing one of the most elegant chemical experiments of all time<\/em>.<\/p>\n

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

    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.\u00a0\u00a0\u00a0(how?<\/strong> [Note 4<\/a>])\u00a0<\/em><\/p>\n

    Roberts’ group carried out the reaction under conditions reported previously, and found that about 50% of the product ended up with the NH2<\/sub> attached to the labelled carbon, and the other 50% had the NH2<\/sub> on the carbon adjacent<\/strong>\u00a0to the label.<\/p>\n

    \"classic<\/p>\n

    This is not<\/strong> consistent with an addition-elimination mechanism!<\/p>\n

    In fact, the roughly 50:50 ratio of products implies the involvement of a\u00a0symmetrical\u00a0<\/em>intermediate which is attacked equally on either side.<\/p>\n

    Roberts’ proposal – which has stood the test of time – was the involvement of\u00a0a short-lived intermediate bearing a carbon-carbon triple bond:\u00a0\u00a0“Benzyne” !\u00a0<\/em><\/strong><\/p>\n

    \"benzyne<\/p>\n

    At first glance, this seems crazy. A triple bond in an aromatic ring?<\/em><\/p>\n

    Well, it’s not quite a\u00a0true\u00a0<\/em>triple bond in the way that we’re familiar with (i.e. with alkynes). Instead of an overlap between two\u00a02p<\/em> orbitals (as in an alkyne) the “triple bond” is formed through overlap of two adjacent sp<\/em>2<\/sup> orbitals in the plane of the ring\u00a0<\/strong>(i.e. at right angles to, and completely independently of, the aromatic pi system).<\/p>\n

    \"orbital<\/p>\n

    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.<\/p>\n

    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).<\/p>\n

    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”.<\/p>\n

    \"in<\/p>\n

    [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].\u00a0<\/em><\/span><\/p>\n

    However strange it might look, the benzyne intermediate explains all of these important observations, and more.<\/p>\n