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This is a question from the Cambridge International Examinations October/November 2017 (pdf from papers.gceguide.com, pdf via the Wayback Machine).

I need to understand why the secondary amine in the serotonin molecule does not undergo condensation reaction with $\ce{CH3COCl}$.
Because, as far as I know, there should be an amide formation for this reaction.

Here's a picture of serotonin:

serotonin with highlighted NH group

I must be lacking some information making that $\ce{NH}$ unsuitable for this reaction. And I know that the other amine and the phenol reacts with $\ce{CH3COCl}$.

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  • $\begingroup$ Secondary amine group shown here is quite sterically hindered..Approach at Burgi-Dunitz trajectory would most probably be difficult $\endgroup$
    – Yusuf Hasan
    Commented Apr 29, 2019 at 9:16
  • $\begingroup$ Did you mean lone pair of electron in N is less available for carbocation to be attacked? @YUSUFHASAN $\endgroup$
    – Amar30657
    Commented Apr 29, 2019 at 9:27
  • $\begingroup$ No..I mean what you have in mind is a nucleophilic attack by NH on CH3COCl as the first step, right? So that would be retarded by steric hindrance.. $\endgroup$
    – Yusuf Hasan
    Commented Apr 29, 2019 at 9:29
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    $\begingroup$ Nothing to do with sterics. The lone pair on the nitrogen is delocalised into the aromatic system so is not available for nucleophilic attack. If you want to functionalise the indole-NH you generally have to formally deprotonate with strong base. Otherwise it reacts as an enamine through the 3-position. $\endgroup$
    – Waylander
    Commented Apr 29, 2019 at 9:53
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    $\begingroup$ @Amar30657 You need to read more about aromatic systems. en.wikipedia.org/wiki/Indole $\endgroup$
    – Waylander
    Commented Apr 29, 2019 at 10:05

2 Answers 2

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The heterocycle in this question is indole and is aromatic. This means that the N lone pair is delocalised and not readily available for nucleophilic attack. Think of it as similar in reactivity to a secondary amide nitrogen RCONHR. Generally you need to formally deprotonate to functionalise, though there are some interesting techniques using carbonyl azoles catalysed by DBU[1] and others using aldehyde and alcohol substrates.[2] Note that 3-unsubstituted indoles react with acyl halides by F-C acylation at the 3 position.[3]

References:

  1. Heller, S. T.; Schultz, E. E.; Sarpong, R. Chemoselective N-Acylation of Indoles and Oxazolidinones with Carbonylazoles. Angew. Chem. Int. Ed. 2012, 51 (33), 8304–8308 DOI: 10.1002/anie.201203976.
  2. Maki, B. E.; Scheidt, K. A. Single-Flask Synthesis ofN-Acylated Indoles by Catalytic Dehydrogenative Coupling with Primary Alcohols. Org. Lett. 2009, 11 (7), 1651–1654 DOI: 10.1021/ol900306v. PMID: 19320508 (with free text available).
  3. Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. A General Method for Acylation of Indoles at the 3-Position with Acyl Chlorides in the Presence of Dialkylaluminum Chloride. Org. Lett. 2000, 2 (10), 1485–1487 DOI: 10.1021/ol005841p.
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If you consider the lone pair on that N-atom and apply Hückel's (4n+2)π-e rule to check aromaticity , it satisfies all the conditions. So in order to achieve aromatic-stabilisation the nitrogen's valency is no more available for condensation!

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